Review

The Role of the Vascular System in Degenerative Diseases:

Mechanisms and Implications
Abdullah Md. Sheikh 1,*, Shozo Yano 1, Shatera Tabassum 1 and Atsushi Nagai 1,2

1 Department of Laboratory Medicine, Shimane University Faculty of Medicine, 89-1 Enya Cho,
Izumo 693-8501, Japan; [email protected] (S.Y.); [email protected] (S.T.);
[email protected] (A.N.)
2 Department of Neurology, Shimane University Faculty of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan

* Correspondence: [email protected]; Tel.: +81-0853-20-2306

Abstract: Degenerative diseases, encompassing a wide range of conditions affecting various organ
systems, pose significant challenges to global healthcare systems. This comprehensive review ex-
plores the intricate interplay between the vascular system and degenerative diseases, shedding light
on the underlying mechanisms and profound implications for disease progression and management.
The pivotal role of the vascular system in maintaining tissue homeostasis is highlighted, as it serves
as the conduit for oxygen, nutrients, and immune cells to vital organs and tissues. Due to the vital
role of the vascular system in maintaining homeostasis, its dysfunction, characterized by impaired
blood flow, endothelial dysfunction, and vascular inflammation, emerges as a common denomina-
tor of degenerative diseases across multiple systems. In the nervous system, we explored the influ-
ence of vascular factors on neurodegenerative diseases such as Alzheimer’s and Parkinson’s, em-
phasizing the critical role of cerebral blood flow regulation and the blood–brain barrier. Within the
kidney system, the intricate relationship between vascular health and chronic kidney disease is scru-
tinized, unraveling the mechanisms by which hypertension and other vascular factors contribute to
renal dysfunction. Throughout this review, we emphasize the clinical significance of understanding
vascular involvement in degenerative diseases and potential therapeutic interventions targeting
vascular health, highlighting emerging treatments and prevention strategies. In conclusion, a pro-
Citation: Sheikh, A.M.; Yano, S.;
found appreciation of the role of the vascular system in degenerative diseases is essential for ad-
Tabassum, S.; Nagaia, A. The Role of
vancing our understanding of degenerative disease pathogenesis and developing innovative ap-
the Vascular System in Degenerative
Diseases: Mechanisms and
proaches for prevention and treatment. This review provides a comprehensive foundation for re-
Implications. Int. J. Mol. Sci. 2024, 25, searchers, clinicians, and policymakers seeking to address the intricate relationship between vascu-
2169. https://doi.org/10.3390/ lar health and degenerative diseases in pursuit of improved patient outcomes and enhanced public
ijms25042169 health.

Academic Editor: Abdelkrim

Keywords: degenerative diseases; vascular system; neurodegenerative disease; chronic kidney
Hmadcha
disease; cardiovascular disease; endothelial dysfunction; inflammation; age-related
Received: 12 January 2024 vascular changes
Revised: 3 February 2024
Accepted: 7 February 2024
Published: 11 February 2024

1. Introduction
Systemic degenerative diseases, characterized by the gradual deterioration of tissues
Copyright: © 2024 by the authors.
and organs over time, exert a significant influence on health and impose a substantial
Licensee MDPI, Basel, Switzerland.
burden not only on individuals but also on society and healthcare systems. The impact of
This article is an open access article
distributed under the terms and
degenerative diseases is expanding due to the increased prevalence of aging populations.
conditions of the Creative Commons Conditions such as Alzheimer’s, Parkinson’s, cardiovascular diseases, and chronic kidney
Attribution (CC BY) license disease (CKD) become more common as life expectancy rises [1–3]. This demographic
(https://creativecommons.org/license shift places immense pressure on healthcare systems and necessitates strategies to effec-
s/by/4.0/). tively manage and treat these chronic diseases.

Int. J. Mol. Sci. 2024, 25, 2169. https://doi.org/10.3390/ijms25042169 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2024, 25, 2169 2 of 22

Due to the impacts on the healthcare system and society, research efforts to compre-
hend the underlying mechanisms of degenerative diseases, develop effective treatments,
and explore preventive measures are gaining importance. Such research highlights the
importance of the interaction and interdependence of different systems on the pathology
of systemic diseases. For communication between the systems, the body relies mainly on
systems like the vascular system [4]. The vascular system plays a crucial role in multiple
physiological processes throughout the body [4]. Dysfunctional vascular mechanisms of-
ten contribute to the initiation and exacerbation of diseases [5–7], highlighting the intricate
relationship between vascular health and overall well-being. Disturbances in the vascular
system can manifest as diseases of specific systems, such as the nervous system or kidney
system [5–7]. Conversely, conditions of a specific system can reciprocally affect the vascu-
lar system [8,9]. Research into the emerging role of the vascular system in contributing to
the development and progression of various degenerative diseases has gained significant
attention in recent years. Here, we provide an overview of some key areas of research and
findings in this field:
i. Neurodegenerative Diseases: There is growing evidence linking vascular health to
neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [10].
Research suggests that compromised blood flow to the brain, often due to conditions
like hypertension and atherosclerosis, can contribute to cognitive decline and neuro-
degeneration.
ii. Cardiovascular Diseases and Metabolic Syndrome: The relationship between cardio-
vascular diseases and metabolic syndrome (a cluster of conditions like obesity, high
blood pressure, high blood sugar, and abnormal cholesterol levels) is well-estab-
lished [11]. These conditions are often intertwined and can collectively contribute to
the progression of degenerative diseases.
iii. Osteoarthritis: Emerging research has started to explore the link between vascular
health and osteoarthritis, a degenerative joint disease [12,13]. Poor blood supply to
joint tissues may contribute to cartilage degeneration and joint inflammation.
iv. Age-Related Macular Degeneration (AMD): AMD is a leading cause of vision loss in
the elderly. Studies have revealed associations between vascular factors, such as hy-
pertension and atherosclerosis, and an increased risk of AMD [14].
v. Chronic Kidney Disease (CKD): Vascular impairment plays a crucial role in the de-
velopment and progression of CKD. Kidneys rely on a rich blood supply, and vascu-
lar damage can lead to renal dysfunction [7,15].
vi. Aging and Vascular Dysfunction: As people age, their blood vessels can undergo
structural and functional changes, which can contribute to the development of vari-
ous degenerative conditions [16]. Understanding the mechanisms behind age-related
vascular dysfunction is a key area of research.
vii. Inflammation and Endothelial Dysfunction: Endothelial cells lining blood vessels
play a crucial role in regulating vascular health. Dysfunction of these cells can lead
to chronic inflammation and contribute to the development of degenerative diseases
[17].
In this review, we discussed the detailed role of the vascular system in systemic de-
generative diseases, with a primary focus on diseases of the cardiovascular, kidney, and
central nervous systems (CNS), as they are integral in understanding the broader impact
of vascular health on systemic degeneration.

2. Vascular System: Anatomy and Functions

2.1. Anatomy
The vascular system, also known as the circulatory system, is a complex network of
blood vessels that circulate blood throughout the body, ensuring the delivery of oxygen,
nutrients, hormones, and immune cells to tissues while removing waste products [4].
Int. J. Mol. Sci. 2024, 25, 2169 3 of 22

Comprising arteries, veins, and capillaries, the vascular system plays a pivotal role in
maintaining physiological equilibrium [4].
i. Arteries: Arteries are thick-walled blood vessels that carry oxygenated blood away
from the heart and distribute it to various tissues. They have a strong muscular layer
that allows them to withstand the force generated by the heart’s contractions. The
largest artery, the aorta, emerges directly from the heart and branches into smaller
arteries that further divide into arterioles [18,19].
ii. Veins: Veins are blood vessels responsible for transporting deoxygenated blood back
to the heart for oxygenation. Unlike arteries, veins have thinner walls and less mus-
cular tissue. They use one-way valves to prevent blood from flowing backward and
rely on skeletal muscle contractions to assist in pushing blood against gravity, par-
ticularly in the limbs. Veins gradually merge into larger vessels, ultimately forming
the superior and inferior vena cava, which return blood to the heart [18,19].
iii. Capillaries: Capillaries are the smallest and most numerous blood vessels, connecting
arteries and veins within tissues. They facilitate the exchange of gases, nutrients, and
waste products between the blood and surrounding cells. Capillary walls consist of
a single layer of endothelial cells, allowing for efficient diffusion of substances. Im-
portantly, there are structural differences in the capillaries of different organs. For
example, capillaries of the CNS possess tight-junctions, which allows them to be
highly selective to the molecules that can enter CNS parenchyma. Oxygen and nutri-
ents pass from capillaries into tissues, while waste products enter the capillaries for
eventual elimination [18,19].

2.2. Functions
The vascular system serves a multitude of crucial functions, including (i) transporting
oxygen, nutrients, and waste products, as well as (ii) maintaining homeostasis, which is
fundamental to maintaining the overall health and function of the body [4,18,19] (Figure
1A). The relationship between the vascular system and degenerative diseases underscores
the significance of its proper function in preventing and managing these conditions.

Figure 1. Normal vessel functions and effects of vascular dysfunctions on degenerative diseases. (A)
The main functions of blood vessels encompass the transportation of oxygen, food and nutrients,
Int. J. Mol. Sci. 2024, 25, 2169 4 of 22

and biomolecules, including hormones, to tissues and organs. Another crucial role is maintaining
organ and tissue homeostasis for proper functionality. Functioning tissues and organs produce
waste products, which are primarily cleared through vessels. Additionally, vessels play a vital role
in tightly regulating temperature and electrolyte levels. Additionally, the vascular endothelium ex-
hibits vasodilatory, anti-proliferative, anti-coagulative, and anti-inflammatory properties. Under
appropriate signals, it can become proliferative for angiogenesis, contribute to inflammation
through expression of adhesion molecules and cytokines, and aid in coagulation, which are essential
for healing processes. (B) Dysfunctional vessels, by hindering the transportation of food, electrolytes,
and nutrients, can induce metabolic changes in organs and tissues. Vascular dysfunction may lead
to oxygen deprivation, causing hypoxic changes in tissues and organs. Failure to transport hor-
mones can also impact organ functions. The anti-inflammatory and anticoagulative properties may
alter vascular dysfunction in a way that influences degenerative diseases. Importantly, the failure to
clear waste through vessel processes can trigger degenerative diseases, particularly neurodegener-
ative diseases. Local vascular inflammation or vessel rupture can also impact tissues and organs,
potentially resulting in degenerative diseases. Notably, pathological angiogenesis can initiate sev-
eral degenerative processes.

(i) Transporting Oxygen, Nutrients, and Waste Products: One of the primary functions
of the vascular system is to facilitate the transportation of oxygen and nutrients to the
tissues and organs. In the tissue capillaries, oxygen and nutrients diffuse from the
blood into the surrounding cells, providing energy for cellular processes. Conversely,
waste products, including carbon dioxide and metabolic byproducts, are exchanged
at the capillary bed and flow back to the heart, where they are then pumped to the
lungs for oxygenation and to other elimination organs for waste removal.
(ii) Maintaining Homeostasis: The vascular system plays a crucial role in maintaining
homeostasis through the regulation of body temperature by redistributing blood
flow to dissipate or conserve heat. It also contributes to fluid balance by controlling
the movement of water and electrolytes between blood and tissues. In response to
injuries, the vascular system initiates clotting processes to prevent excessive bleeding.
Additionally, blood vessels participate in immune responses by transporting im-
mune cells to areas of infection or injury, contributing to the body’s defense mecha-
nisms.

3. Vascular Dysfunction in Degenerative Diseases

Vascular dysfunction encompasses a range of impaired functions within blood ves-
sels, including endothelial dysfunction, inflammation, oxidative stress, impaired angio-
genesis, and irregular vessel structure [20–22]. In the context of degenerative diseases,
vascular dysfunction assumes profound significance as it often serves as a common ele-
ment connecting various disease processes across different body systems (Figure 1B). The
compromised blood flow, insufficient nutrient delivery, and impaired waste removal
linked to vascular dysfunction contribute to tissue damage, cellular stress, and declining
functionality (Figure 1B). For instance, in cardiovascular diseases, vascular dysfunction
plays a pivotal role in the development of conditions like atherosclerosis, hypertension,
and heart failure [23–25]. In neurodegenerative diseases, such as Alzheimer’s disease, vas-
cular dysfunction disrupts the delicate balance of nutrient supply and waste removal, in-
cluding the clearance of amyloid β (Aβ) in the brain [26,27]. This acceleration of neuro-
degeneration contributes to cognitive decline. Moreover, vascular dysfunction signifi-
cantly influences renal degenerative diseases. In conditions like chronic kidney disease
(CKD) and diabetic nephropathy, compromised blood flow within the kidneys leads to
tissue damage and reduced filtration capacity [28,29]. Endothelial dysfunction and inflam-
mation further exacerbate kidney dysfunction, underscoring the critical role of the vascu-
lar system in maintaining renal health. Recognizing the role of vascular dysfunction has
profound implications for understanding the pathologies of degenerative diseases. In this
section, we discussed the specific contributions of vascular dysfunction to degenerative
diseases within different body systems.
Int. J. Mol. Sci. 2024, 25, 2169 5 of 22

3.1. Cardiovascular System

Impaired vascular function plays a pivotal role in the onset and progression of cardi-
ovascular degenerative diseases, including hypertension, atherosclerosis, and heart fail-
ure. These conditions, collectively known as cardiovascular diseases (CVD), impose a sig-
nificant burden on healthcare systems in terms of morbidity, mortality, and associated
costs. An estimate suggests that globally, CVD accounted for 19.05 million deaths in 2020,
marking an 18.71% increase from 2010. The prevalence of CVD cases in 2020 was 607.64
million, indicating a rise of 29.01% from 2010 [30]. In the subsequent year (2021), the esti-
mation of CVD-related deaths increased to 20.5 million, representing close to one-third of
all global deaths, showcasing an upward trend that began during the 1990s [31]. The prev-
alence of CVD also showed an increasing trend, reaching 621 million in 2021, up by 2.19%
from 2020 [32].
CVD not only exacts a social toll through disease occurrence and mortality but also
places a significant strain on the economy and healthcare systems. In the USA, the cost of
cardiovascular diseases amounted to USD 555 billion in 2015, comprising USD 318 billion
in direct costs and $237 billion in indirect costs [33]. This figure is projected to escalate to
USD 1.1 trillion by 2035. Moreover, the costs associated with informal caregiving for CVD
patients were estimated at USD 61 billion in 2015 and are expected to rise to USD 128
billion by 2035 [33]. Notably, approximately four out of every five CVD-related deaths
occur in low- and middle-income countries, exacerbating the strain on already over-
stretched healthcare systems in those regions [31]. Consequently, the economic burden of
CVD could significantly impede healthcare systems, impacting not only CVD manage-
ment but also other health conditions. To mitigate such immense strain on the healthcare
system and the economy, preventive measures to improve vascular health could be crucial
in managing the burden of CVD in both sectors.
To improve vascular health, a thorough understanding of vascular functions and
how their dysfunctions contribute to the onset of CVD is essential. The intricate relation-
ship between vascular dysfunction and conditions such as hypertension, atherosclerosis,
and heart failure, which are described below, underscores the importance of maintaining
healthy blood vessels for the overall management of CVD.
(i) Hypertension: Vascular dysfunction is a key contributor to the onset and mainte-
nance of hypertension. Endothelial dysfunction is frequently seen in hypertensive
conditions [24], where it results in narrowed blood vessels and elevated systemic re-
sistance, causing blood pressure to increase [30]. Additionally, vascular dysfunction
and the renin–angiotensin–aldosterone system, a hormonal pathway that regulates
blood pressure, can affect each other bidirectionally. Dysregulation of this system
due to impaired vascular function can lead to sustained high blood pressure levels,
further damaging blood vessel walls and promoting hypertensive complications
[31,32].
(ii) Atherosclerosis: Impaired vascular function is intimately linked to the development
of atherosclerosis, a condition characterized by focal inflammation and the accumu-
lation of oxidized-LDL-laden plaques within arterial walls [33]. Endothelial dysfunc-
tion triggers inflammatory processes, attracting immune cells, including macro-
phages and T-cells, that contribute to plaque formation [23,34]. As plaques grow, the
arterial lumen narrows, reducing blood flow and causing turbulence that further en-
hances the endothelial inflammatory condition. This cycle of inflammation, plaque
buildup, and arterial narrowing creates a hostile environment conducive to blood
clot formation, increasing the risk of myocardial infarction and strokes.
(iii) Heart Failure: Vascular dysfunction significantly contributes to the progression of
heart failure [25]. Chronic hypertension and atherosclerosis, driven by impaired vas-
cular function, strain the heart by requiring it to pump against increased resistance,
leading to cardiac enlargement, especially left ventricular hypertrophy. Additionally,
vascular dysfunctions impact the blood vessels within the heart, which can lead to
Int. J. Mol. Sci. 2024, 25, 2169 6 of 22

reduced oxygen and nutrient delivery, further weakening cardiac function [35]. The
increased workload, impaired coronary blood flow, and inflammatory signals can
also contribute to the development of heart failure with preserved ejection fraction
(HFpEF), a type of heart failure characterized by impaired relaxation of the heart’s
chambers [36].

3.2. Nervous System

Impaired vascular function plays a significant role in the development and progres-
sion of degenerative diseases affecting the brain, including Alzheimer’s disease, stroke,
cerebral small vessel diseases, and Parkinson’s disease. The intricate interplay between
vascular health and these neurological conditions highlights the importance of maintain-
ing optimal blood vessel function for brain well-being.
(i) Alzheimer’s Disease: Vascular dysfunction is closely linked to the pathogenesis of
Alzheimer’s disease (AD), a neurodegenerative disorder characterized by cognitive
decline and memory loss. Deposition of aggregated amyloid β (Aβ) peptide is con-
sidered the main cause of AD [37]. In normal brains, Aβ is cleared mainly through
perivascular pathways [38]. Dysfunctional blood vessels contribute to reduced Aβ
clearance, leading to increased aggregation and deposition [5]. Such deposited Aβ
further impairs cerebral blood flow and causes pathological angiogenesis, blood–
brain barrier disruption, neuroinflammation, and impaired clearance of toxic protein
aggregates, including aggregated Aβ peptide [5,6,39].
(ii) Stroke: Impaired vascular function significantly increases the risk of stroke. Endothe-
lial dysfunction compromises blood vessel dilation and responsiveness, promoting
the development of blood clots [40]. Atherosclerosis, driven by vascular dysfunction,
can lead to plaque rupture, triggering clot formation and embolic strokes [33]. Fur-
thermore, chronic hypertension could cause sclerosis and damage the blood vessels,
increasing the likelihood of vessel rupture and hemorrhagic strokes [41]. The role of
vascular dysfunction in both ischemic and hemorrhagic stroke underscores its impact
on overall brain health.
(iii) Cerebral Small Vessel Diseases: Cerebral small vessel diseases encompass a group of
conditions that affect the small blood vessels within the brain. Impaired vascular
function contributes to the development of these diseases, including arteriolosclero-
sis and cerebral microbleeds [42]. Endothelial dysfunction, inflammation, and oxida-
tive stress compromise the structural integrity of these small vessels, leading to vessel
wall thickening, narrowing, and increased fragility [42–44]. The cumulative effect of
vascular dysfunction in cerebral small vessel diseases disrupts cerebral blood flow,
which can result in lacunar infarcts and contribute to cognitive impairment, mobility
issues, and other neurological deficits.
(iv) Parkinson’s Disease: Vascular dysfunction also holds implications for Parkinson’s
disease (PD), a neurodegenerative disorder characterized by motor symptoms like
tremors and rigidity. In PD, the primary pathology involves the degeneration of do-
paminergic neurons in the substantia nigra region of the midbrain. The key diagnos-
tic histopathological features of PD are intraneuronal Lewy bodies containing aggre-
gated α-synuclein, leading to the belief that such aggregation is the primary cause of
neurodegeneration and, consequently, the disease [45]. In the context of aggregation,
an altered protein quality control system, especially the ubiquitin-proteasome path-
way, is thought to play a crucial role in PD [46,47]. Numerous studies have implicated
vascular changes, including impaired blood-brain barrier function and pathological
angiogenesis, in the development of the pathological changes seen in PD [48–51].
These changes result in hypoperfusion. Given that hypoperfusion can impact the pro-
tein quality control system, including the ubiquitin-proteasome system, it is plausible
that decreased blood flow to the substantia nigra may contribute to α-synuclein ag-
gregation. Moreover, hypoperfusion can subject cells to stress, potentially triggering
Int. J. Mol. Sci. 2024, 25, 2169 7 of 22

the aggregation process of α-synuclein. Furthermore, impaired vascular health dis-

rupts the supply of oxygen and nutrients, which can expedite neuronal damage in
this vulnerable region.

3.3. Kidney System

Impaired vascular function plays a significant role in the development and progres-
sion of various kidney degenerative diseases, including chronic kidney disease (CKD),
diabetic kidney disease, and hypertensive nephropathy. The intricate relationship be-
tween vascular health and these conditions underscores the importance of maintaining
optimal blood vessel function for kidney well-being.
(i) Chronic Kidney Disease (CKD): Impaired vascular function contributes to the path-
ogenesis and progression of CKD. The disease is a long-term medical condition char-
acterized by the gradual and irreversible deterioration of kidney function over an
extended period, typically months to years. CKD is often categorized into different
stages based on the level of kidney function, with stage 1 being the mildest and stage
5 representing end-stage renal disease (ESRD), where kidney function is severely im-
paired, and patients usually require dialysis or a kidney transplant to survive [52].
Common causes of CKD include diabetes, hypertension, glomerulonephritis, poly-
cystic kidney disease, and certain other medical conditions [53]. Hypertension can
lead to increased resistance to blood flow. This can damage the delicate blood vessels
in the kidneys over time, impairing their ability to filter waste and regulate fluids [54].
Additionally, atherosclerosis and endothelial dysfunction are often seen in individu-
als with CKD, which affect the kidney perfusion and ability to regulate blood flow
and maintain an appropriate balance of vasodilation and constriction [54,55]. This
results in reduced blood flow to the kidneys. Moreover, chronic inflammation asso-
ciated with vascular dysfunction can promote fibrosis and scarring within the kidney
tissues. As a result, kidney function gradually declines over time.
(ii) Diabetic Kidney Disease: Diabetic kidney disease, also referred to as diabetic
nephropathy, represents a prevalent complication of diabetes. Poorly controlled dia-
betes can directly inflict harm upon the glomeruli and renal blood vessels [56]. Addi-
tionally, advanced glycation end products (AGEs) can harm blood vessels by trigger-
ing the generation of reactive oxygen species (ROS) and fostering inflammation
[56,57]. Elevated blood sugar levels result in injury to the blood vessels that provide
the kidneys, ultimately causing endothelial dysfunction and inflammation.
(iii) Hypertensive Nephropathy: Hypertensive nephropathy results from chronic hyper-
tension damaging the blood vessels within the kidneys [58]. Vascular dysfunction
plays a key role in its progression. Elevated blood pressure causes structural changes
in the small blood vessels, leading to arteriosclerosis and narrowing of the renal ar-
teries [59]. These changes reduce blood flow to the kidneys, triggering a cascade of
events that contribute to kidney damage. The decreased blood flow prompts the kid-
neys to release hormones that raise blood pressure further, creating a vicious cycle
[58,59]. The compromised blood vessels also impair the kidneys’ ability to filter waste
and maintain fluid and electrolyte balance, ultimately leading to kidney dysfunction.
From these findings, it is evident that impaired vascular function significantly con-
tributes to the development and progression of cardiovascular, neurological, and kidney
degenerative diseases. Furthermore, the vascular system exerts a similar impact on all
other systems of the body. The consequences of endothelial dysfunction, inflammation,
and reduced blood flow within the organs or tissues culminate in tissue damage, fibrosis,
and functional decline. Recognizing the pivotal role of vascular health underscores the
importance of preserving blood vessel function as a potential target for preventing and
managing degenerative conditions. Strategies aimed at improving vascular health, which
encompass blood pressure management, glycemic control, and lifestyle modifications,
Int. J. Mol. Sci. 2024, 25, 2169 8 of 22

hold promise for mitigating degenerative disease progression and enhancing health out-
comes.

4. Molecular Mechanisms Linking Vascular Dysfunction and Degenerative Diseases

The molecular mechanisms linking degenerative diseases and vascular dysfunction
are complex and multifaceted, and they can vary depending on the specific disease and
organ system involved. However, some common molecular mechanisms are involved in
the interplay between vascular dysfunction and degenerative diseases (Figure 2).

Figure 2. Molecular mechanisms of vascular dysfunction. Several mechanisms of vascular dysfunc-

tion have been implicated, and these mechanisms play a crucial role in vascular conditions such as
atherosclerosis and hypertension. One significant molecular aspect of vascular dysfunction is endo-
thelial dysfunction. The causes of endothelial dysfunction include reduced nitric oxide (NO) bioa-
vailability, vascular inflammation, and dyslipidemia. In the context of vascular inflammation, endo-
thelial cells can express adhesion molecules and cytokines, impacting the degenerative processes of
organs and tissues. Additionally, growth factors have the potential to induce smooth muscle cell
proliferation and extracellular matrix production, leading to sclerosis and hypoperfusion. Vasoac-
tive molecules such as endothelin-1 or Angiotensin II can also exert effects on vessels. Moreover,
certain signaling systems have been identified as crucial contributors to vascular dysfunction.
Int. J. Mol. Sci. 2024, 25, 2169 9 of 22

4.1. Endothelial Dysfunction

The properties of healthy endothelial cells are anti-proliferative to smooth muscle
cells, anti-coagulative, vasodilatory, and anti-adhesive to inflammatory cells [60,61]. En-
dothelial dysfunction is a complex process involving various molecular mechanisms, sig-
naling pathways, and molecules [61]. It is a key contributor to the development and pro-
gression of many vascular diseases, including atherosclerosis, hypertension, and diabetic
vascular complications [61–63]. Figure 3 depicted the common molecular mechanisms of
endothelial dysfunction. Molecular mechanisms involved in endothelial dysfunction in-
clude:
(i) Oxidative Stress: Excessive production of reactive oxygen species (ROS), such as the
superoxide anion (O2·-) and hydrogen peroxide (H2O2), can inflict damage upon en-
dothelial cells and impair the bioactivity of nitric oxide (NO) [64]. Nitric oxide is a
molecule that fosters vasodilation, thereby promoting vascular health [64]. Also, su-
peroxide can interact with NO and generate peroxynitrite (ONOO-), which can simi-
larly inflict harm upon these cells [65]. The activation of NADPH oxidases (NOX) and
xanthine oxidase is commonly implicated in the generation of these ROS species, a
phenomenon observed within endothelial cells in numerous degenerative diseases
[66,67].
(ii) Inflammation: Chronic inflammation, characterized by elevated levels of proinflam-
matory cytokines (such as TNF-α, IL-1β), chemokines (MCP-1), adhesion molecules
(VCAM-1, ICAM-1), and inflammatory receptors (Toll-like receptors, TNF receptors),
can be induced in inflammatory conditions [17,21]. Through the action of adhesion
molecules, chemokines, and their receptors, proinflammatory cells are recruited to
the affected area. Inflammatory cytokines and their receptors typically activate pro-
inflammatory transcription systems, including NF-κB, AP-1, and STATs [68]. This ac-
tivation leads to the production of more proinflammatory cytokines, chemokines,
and growth factors in these cells, as well as in endothelial cells, disrupting their nor-
mal function. Additionally, inflammatory mediators can impair the synthesis of nitric
oxide (NO) and promote vasoconstriction [69]. These effects create a vicious cycle
that profoundly alters endothelial cell properties. Furthermore, low-density lipopro-
tein (LDL) cholesterol can undergo oxidation by reactive oxygen species (ROS) and
infiltrate the endothelium. This triggers an inflammatory response and the formation
of atherosclerotic plaques, which can narrow and stiffen blood vessels [33].
(iii) Nitric Oxide (NO) Bioavailability: Nitric oxide (NO), synthesized by endothelial ni-
tric oxide synthase (eNOS), is a key endogenous vasodilator crucial for maintaining
proper vascular function [70]. Dysregulation of eNOS activity, whether through
mechanisms like eNOS uncoupling or reduced eNOS expression, results in reduced
NO bioavailability [69–71]. This, in turn, hinders vasodilation and promotes vasocon-
striction.
(iv) Endoplasmic Reticulum Stress: Accumulating evidence suggests that endoplasmic
reticulum (ER) stress is one of the primary causes of endothelial dysfunction [72]. The
buildup of misfolded proteins within the ER triggers unfolded protein response
(UPR) pathways, which in turn contribute to endothelial dysfunction, inflammation,
and apoptosis [72].
Int. J. Mol. Sci. 2024, 25, 2169 10 of 22

Figure 3. Molecular mechanisms of endothelial dysfunction. In a healthy state, endothelial cells ex-
hibit anti-proliferative, vasodilatory, anti-inflammatory, anti-coagulant, and anti-inflammatory cell
adhesion properties. However, several conditions, including elevated levels of low-density lipopro-
tein (LDL), mechanical stress on the vessel wall caused by hypertension or turbulent flow at arterial
bifurcations, chronic generalized inflammatory conditions, hyperglycemia, and related products,
can trigger endothelial dysfunction. Elevated LDL levels in the bloodstream can infiltrate the vessel
wall where they become oxidized. Oxidized LDL activates endothelial cells to express cytokines
(INFγ, TNFα), chemokines (MCP-1, IP-10), adhesion molecules (ICAM-1, VCAM-1), and growth
factors (PDGF), which act in an autocrine and paracrine manner. Additionally, oxidized LDL acts
as a chemoattractant for inflammatory macrophages. The chemokines produced by endothelial cells,
along with oxidized LDL, induce the chemotactic accumulation of inflammatory cells, including
macrophages and T cells. Furthermore, cytokines, in conjunction with oxidized LDL, activate mac-
rophages and T cells to produce more cytokines and chemokines. Activated endothelial cells and
inflammatory cells also produce growth factors that stimulate the proliferation of vascular smooth
muscle cells and remodel the vessel wall. These smooth muscle cells are also activated by cytokines
and participate in the inflammatory process. Additionally, inflammatory cells produce various pro-
teases that remodel the vessel wall and affect the local inflammatory condition and coagulation sys-
tem. Moreover, cytokines and oxidized LDL inhibit the production of nitric oxide (NO) from endo-
thelial cells, which is one of the main vasodilatory signals for vessels. These events initiate a vicious
cycle whereby endothelial cells acquire proliferative, inflammatory cell adhesive, pro-coagulant, re-
duced vasodilation, and inflammatory cytokine, chemokine, and growth factor-producing proper-
ties. ICAM-1 = intercellular adhesion molecule-1, VCAM-1 = vascular cell adhesion molecule-1,
INFγ = interferon γ, TNFα = tumor necrosis factor α, MCP-1 = monocyte chemoattractant protein-1,
IP-10 = INFγ-induced protein-10, PDGF = platelet-derived growth factor.

4.2. Atherosclerosis
Atherosclerosis is a common feature of many degenerative diseases, particularly car-
diovascular diseases. It involves the accumulation of lipids, including oxidized LDL, im-
mune cells, and fibrous tissue, within the arterial walls, leading to narrowing of the lumen
and hypoperfusion supplying area and affecting the degenerative process [23,33]. Addi-
tionally, the molecular mechanism of atherosclerosis is not limited to the cardiovascular
system; it can have systemic effects and contribute to the pathogenesis of degenerative
diseases in multiple organ systems [55]. Here are some of the key signaling pathways and
mechanisms through which atherosclerotic vessels can impact other systems:
Int. J. Mol. Sci. 2024, 25, 2169 11 of 22

(i) Inflammation and Immune Responses: Cytokines and chemokines: Atherosclerosis is

characterized by chronic inflammation within arterial walls. Inflammatory mediators,
such as cytokines (e.g., TNF-α, IL-1β) and chemokines, can enter the bloodstream,
leading to systemic inflammation [33,73].
(ii) Immune Cell Activation: In response to atherosclerotic plaques, immune cells like T-
cells, monocytes, and macrophages become activated and release proinflammatory
cytokines [74]. These activated immune cells can then circulate throughout the body,
contributing to systemic inflammation [23,33,74].
(iii) Endothelial Dysfunction and Impaired Nitric Oxide (NO) Bioavailability: Atheroscle-
rosis can lead to endothelial dysfunction, reducing the production and availability of
NO, a molecule important for vasodilation and maintaining vascular health [70,71].
This endothelial dysfunction can affect blood flow throughout the body.
(iv) Oxidative Stress: Atherosclerotic vessels generate high levels of reactive oxygen spe-
cies (ROS) through processes like LDL oxidation and activation of NADPH oxidases
[63,64]. These ROS can cause oxidative stress, which can damage tissues and contrib-
ute to the development of systemic diseases.
(v) Platelet Activation and Thrombosis: Atherosclerotic plaques can rupture, leading to
the exposure of pro-thrombotic substances. Platelets can become activated and con-
tribute to thrombosis, potentially causing strokes or myocardial infarctions [75].
The systemic effects of atherosclerotic vessels on degenerative diseases in other sys-
tems underscore the importance of a holistic approach to managing and preventing ath-
erosclerosis. Addressing risk factors and promoting vascular health can have a significant
impact on overall health and reduce the risk of degenerative diseases in multiple organ
systems.

4.3. Hypertension
The molecular signaling pathways through which hypertension affects degenerative
diseases are complex and can vary depending on the specific disease and tissues involved.
However, several key molecular mechanisms and signaling pathways have been identi-
fied that contribute to the relationship between hypertension and degenerative diseases:
(i) Renin–Angiotensin–Aldosterone System (RAAS): The RAAS is a central regulator of
blood pressure and fluid balance [76]. In hypertension, there is often an overactiva-
tion of the RAAS. This system involves the release of renin from the kidneys, which
leads to the conversion of angiotensinogen to angiotensin I and then angiotensin II.
Angiotensin II is a potent vasoconstrictor and can promote inflammation and oxida-
tive stress, contributing to vascular damage, atherosclerosis, and organ damage. An-
giotensin II also stimulates the release of aldosterone, which can lead to sodium and
water retention, further increasing blood pressure and strain on the cardiovascular
system [76–78].
(ii) Inflammation Signaling: Hypertension is associated with chronic low-grade inflam-
mation [17,79,80]. Molecular signaling pathways involving cytokines, chemokines,
and inflammatory mediators, such as IL-1β, NF-kB, and TNF-α, play a role in the
inflammatory response [80,81]. This chronic inflammation can contribute to the de-
velopment and progression of degenerative diseases by damaging tissues and pro-
moting atherosclerosis.
(iii) Oxidative Stress: Increased blood pressure can lead to increased production of reac-
tive oxygen species (ROS) in blood vessels and tissues. Molecular pathways related
to oxidative stress, such as those involving NADPH oxidase and superoxide dis-
mutase, are implicated [82]. Oxidative stress can damage cellular components, in-
cluding DNA, lipids, and proteins, contributing to cellular dysfunction and degener-
ative diseases.
(iv) Endothelial Dysfunction: Hypertension can impair the function of endothelial cells
that line blood vessels [24,30,32]. Signaling pathways involving nitric oxide (NO),
Int. J. Mol. Sci. 2024, 25, 2169 12 of 22

which is a vasodilator, and endothelin-1 (ET-1), a vasoconstrictor, are altered in en-

dothelial dysfunction. This dysfunction can lead to vasoconstriction, inflammation,
and atherosclerosis.
(v) Cellular Growth and Hypertrophy: Chronic high blood pressure can lead to hyper-
trophy of cardiac muscle cells through signaling pathways involving proteins like
mTOR (mammalian target of rapamycin) and calcineurin [83]. Cardiac hypertrophy
can eventually lead to heart failure and increase the risk of cardiac degenerative dis-
eases.
(vi) Neuroinflammation and Brain Damage: In the context of hypertension-related brain
damage and neurodegenerative diseases, signaling pathways involving microglia ac-
tivation, cytokines, and amyloid-beta protein processing are implicated [84]. Chronic
hypertension can promote neuroinflammation and contribute to the pathogenesis of
conditions like Alzheimer’s disease and vascular dementia [84,85].

4.4. Environment and Endocrine Disruptors

The environment in which we live exerts a profound influence on our health. Pollu-
tion, exposure to toxic chemicals, dietary habits, and lifestyle choices all contribute to the
complex interplay between environmental factors and disease development [86]. Of par-
ticular concern are endocrine disruptors, substances that interfere with hormone function
and have been implicated in a myriad of health problems. These disruptors, found in plas-
tics, pesticides, personal care products, and other consumer goods, can disrupt the deli-
cate balance of the endocrine system, potentially contributing to both vascular disease and
degenerative conditions. Mounting evidence suggests that exposure to endocrine disrup-
tors may increase the risk of vascular diseases such as atherosclerosis and hypertension
[87]. Chemicals like bisphenol A (BPA), phthalates, and polychlorinated biphenyls (PCBs)
have been linked to endothelial dysfunction, inflammation, and oxidative stress, all of
which are key drivers of vascular pathology [87,88]. Moreover, endocrine disruptors can
cause dysregulated vascular smooth muscle cell responses, further exacerbating the pro-
gression of vascular disease [89].
In addition to their impact on vascular health, endocrine disruptors have also been
implicated in the pathogenesis of degenerative diseases. Epidemiological and experi-
mental studies have revealed associations between exposure to these compounds and the
development of Alzheimer’s, Parkinson’s, and certain types of cancer [90–93]. Disruption
of hormone signaling pathways and insulin resistance, endothelial dysfunction, oxidative
stress, chronic inflammation, alterations in lipid metabolism, and mitochondrial dysfunc-
tion are among the proposed mechanisms by which endocrine disruptors contribute to
degenerative conditions [94–96]. Given the interconnected nature of vascular disease and
degenerative diseases, it is plausible that common environmental factors, including endo-
crine disruptors, may underlie their shared pathophysiology.

5. Common Risk Factors that Affect Vascular System and Degenerative Diseases
Many common risk factors contribute to both vascular dysfunction and the develop-
ment of degenerative diseases. These risk factors often overlap and can exacerbate one
another, increasing the overall risk of various health problems. Here, we discussed some
of the key risk factors that are associated with both vascular dysfunction and degenerative
diseases:
i. Aging: The aging process itself is a significant risk factor for both vascular dysfunc-
tion and degenerative diseases [97,98]. As people age, their blood vessels naturally
undergo structural and functional changes, becoming less elastic and more suscepti-
ble to damage [99]. This contributes to conditions like arterial stiffness and an in-
creased risk of atherosclerosis, which can affect both the heart and other organs.
ii. Hypertension: Hypertension is a common risk factor for both vascular dysfunction
and degenerative diseases [24,30,41,43,54]. Chronic high blood pressure can damage
Int. J. Mol. Sci. 2024, 25, 2169 13 of 22

the walls of arteries, making them less elastic and more prone to atherosclerosis. It
also increases the risk of conditions like stroke, heart disease, and kidney disease.
iii. Smoking: Smoking is a major risk factor for vascular dysfunction and degenerative
diseases [99,100]. It constricts blood vessels, increases oxidative stress, increases
blood coagulability, reduces oxygen delivery to tissues, and promotes the develop-
ment of atherosclerosis. Smoking is strongly associated with cardiovascular diseases,
kidney diseases, lung diseases, and cancers.
iv. Dyslipidemia: An imbalance in blood lipid levels, particularly elevated levels of low-
density lipoprotein (LDL) cholesterol and reduced levels of high-density lipoprotein
(HDL) cholesterol, is also considered a risk factor for various health conditions, in-
cluding vascular dysfunction, atherosclerosis, nervous system diseases such as cere-
bral small vessel diseases, and diabetes [33,101,102]. Dyslipidemia, characterized by
these lipid abnormalities, poses a significant risk for atherosclerosis, a condition that
can affect arteries throughout the body and contribute to vascular dysfunction, as
well as degenerative diseases like heart disease and stroke. Additionally,
dyslipidemia is known to increase overall levels of inflammation and oxidative stress,
negatively impacting not only the health of blood vessels but also the well-being of
other organs.
v. Diabetes: Diabetes, especially type 2 diabetes, is a common risk factor for both vas-
cular dysfunction and degenerative diseases [29,51,62,103]. High blood sugar levels
can damage blood vessels (diabetic vasculopathy), contribute to atherosclerosis, and
increase the risk of heart disease, stroke, and peripheral vascular disease, along with
degenerative diseases of the nervous system, including Alzheimer’s disease.
vi. Obesity: Obesity is associated with several health issues, including insulin resistance,
dyslipidemia, inflammation, and increased blood pressure [104]. These factors col-
lectively contribute to the development of vascular dysfunction and degenerative dis-
eases, such as heart disease, type 2 diabetes, and osteoarthritis.
vii. Physical Inactivity: A sedentary lifestyle is a risk factor for both vascular dysfunction
and degenerative diseases [105]. Lack of physical activity can lead to weight gain,
worsen insulin sensitivity and diabetes, and promote the development of atheroscle-
rosis. Regular exercise, on the other hand, can help improve vascular health and re-
duce the risk of many degenerative diseases.
viii. Poor Diet: A diet high in saturated and trans fats, refined sugars, and processed foods
can contribute to obesity, dyslipidemia, diabetes, and inflammation [106]. These die-
tary factors are associated with an increased risk of both vascular dysfunction and
degenerative diseases.
ix. Chronic Inflammation: Chronic inflammation is a common factor underlying many
degenerative diseases and can also contribute to vascular dysfunction [15,21,34]. In-
flammatory processes can damage blood vessel walls, promote atherosclerosis, and
increase the risk of conditions like rheumatoid arthritis and cardiovascular disease.
x. Stress: Chronic stress can contribute to high blood pressure, unhealthy behaviors (e.g.,
overeating or smoking), and the release of stress hormones that can affect blood ves-
sel function [106,107]. Over time, this can contribute to both vascular dysfunction and
degenerative diseases.

6. The Impact of Degenerative Diseases on Vascular Dysfunction

The relationship between the vascular system and degenerative diseases is bidirec-
tional and complex. Vascular dysfunction can contribute to the development and progres-
sion of degenerative diseases, while degenerative diseases can, in turn, worsen vascular
health. Recognizing and addressing vascular risk factors and promoting vascular health
through lifestyle measures are essential steps in preventing and managing both vascular
dysfunction and degenerative conditions. Here, we discussed some of the degenerative
diseases that impact vascular dysfunction:
Int. J. Mol. Sci. 2024, 25, 2169 14 of 22

i. Diabetes: Diabetes, particularly type 2 diabetes, can lead to vascular dysfunction [62].
High blood sugar levels can damage the endothelial cells lining blood vessels, pro-
moting atherosclerosis and increasing the risk of heart disease, stroke, and peripheral
vascular disease.
ii. Inflammation: Chronic inflammation, a hallmark of many degenerative diseases (e.g.,
rheumatoid arthritis, inflammatory bowel disease), can directly impact the vascular
system [108,109]. Inflammatory processes can damage the endothelium, leading to
endothelial dysfunction and increased risk of atherosclerosis and cardiovascular
events.
iii. Osteoarthritis: In this degenerative joint disease, the wear and tear on joints can lead
to inflammation and damage to nearby blood vessels [12,13]. Chronic inflammation
can contribute to vascular dysfunction in affected joints, exacerbating pain and lim-
iting mobility.
iv. CKD: CKD is both a cause and consequence of vascular dysfunction [52–55]. Kidney
damage can result from prolonged exposure to risk factors like high blood pressure
and diabetes, which also contribute to vascular impairment. In turn, kidney dysfunc-
tion can lead to imbalances in electrolytes and hormones, affecting blood vessel tone
and function.
v. Cerebral Small Vessel Diseases: CSVD primarily affects the small blood vessels in the
brain, leading to white matter lesions, lacunar infarcts, and microbleeds [42–44].
These vascular abnormalities are closely associated with cognitive decline, and they
can disrupt the brain’s ability to function properly. CSVD can lead to both ischemic
and hemorrhagic events in the brain. These events contribute to vascular dysfunction
and can result in stroke-like symptoms and cognitive impairment. Degenerative
changes in small blood vessels can lead to reduced blood flow, increasing the risk of
strokes and vascular dementia.
vi. Alzheimer’s Disease: In AD, cerebral vessel integrity is compromised due to the dep-
osition of Aβ, resulting in cerebral amyloid angiopathy [27,42]. These abnormal pro-
tein deposits can affect blood vessels, reducing cerebral blood flow. Reduced blood
flow deprives brain cells of oxygen and nutrients, contributing to cognitive decline
and memory loss. Some individuals with Alzheimer’s disease also experience vascu-
lar cognitive impairment (VCI), where vascular dysfunction in the brain exacerbates
cognitive deficits. This can occur alongside the neurodegenerative processes in Alz-
heimer’s disease.

7. Therapeutic Implications
Targeting vascular dysfunction is a promising approach to mitigate the progression
of degenerative diseases, including conditions like chronic kidney disease (CKD). Vascu-
lar dysfunction plays a critical role in the pathogenesis of many degenerative diseases,
and addressing it can have a positive impact on disease management. Here, we discussed
some potential therapeutic interventions for degenerative diseases aimed at targeting vas-
cular dysfunction:
i. Blood Pressure Control: Maintaining optimal blood pressure is crucial in managing
vascular dysfunction. Antihypertensive medications, such as angiotensin-converting
enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are often used
to control hypertension and reduce the strain on blood vessels [110]. They can also
help control CKD [111]. Although antihypertensives are not the primary treatment
for CSVD, associated hypertension may worsen the disease, and hypertension con-
trol can show beneficial effects. Some studies have suggested a link between hyper-
tension and an increased risk of developing Alzheimer’s disease [112,113]. Hyperten-
sion may contribute to vascular dysfunction in the brain, which can exacerbate AD-
related cognitive decline.
Int. J. Mol. Sci. 2024, 25, 2169 15 of 22

ii. RAAS Inhibition: Inhibition of the renin–angiotensin–aldosterone system (RAAS) is

a common therapeutic strategy to protect vascular health in conditions like CKD.
Medications like ACE inhibitors and ARBs not only lower blood pressure but also
have direct vascular protective effects by reducing vasoconstriction and inflamma-
tion [111,114].
iii. Antioxidant Therapy: Since oxidative stress plays an important role in most degen-
erative diseases and vascular dysfunction, antioxidant therapy could be a good ad-
junct to the main therapy of a specific degenerative disease [64,66,67]. Antioxidant
supplements or diets rich in antioxidants may help combat oxidative stress, which is
a common contributor to vascular dysfunction. Antioxidants like vitamin C, vitamin
E, and coenzyme Q10 may have beneficial effects in vascular diseases as well as neu-
rodegenerative diseases, including Alzheimer’s disease.
iv. Anti-Inflammatory Medications: Since inflammation plays a significant role in vascular
dysfunction, nonsteroidal anti-inflammatory drugs (NSAIDs) and other anti-inflam-
matory medications may be used to reduce inflammation and alleviate vascular dam-
age [74,79]. Indeed, aspirin has long been used as a preventive measure for cardiovas-
cular diseases due to its anti-inflammatory and anticoagulative effects [115].
v. Lifestyle Modifications: Lifestyle changes, such as adopting a heart-healthy diet, in-
creasing physical activity, and quitting smoking, can improve vascular function and
reduce the risk of degenerative diseases [116].
vi. Exercise Programs: Regular exercise has a positive impact on vascular health. Exer-
cise can improve endothelial function, increase nitric oxide production, and enhance
blood vessel flexibility [116].
vii. Cholesterol Management: High levels of cholesterol, especially low-density lipopro-
tein (LDL) cholesterol, can contribute to atherosclerosis and vascular dysfunction [33].
Statins and other lipid-lowering medications are used to manage cholesterol levels
[117].
viii. Antiplatelet Therapy: Antiplatelet medications, such as aspirin, can help prevent
blood clots and reduce the risk of vascular events like heart attacks and strokes
[118,119].
ix. Stem cell therapy: In recent years, stem cell therapy has emerged as a potential treat-
ment option for degenerative diseases of the future. Stem cells, including embryonic
stem cells, induced pluripotent cells, and tissue-specific stem cells, possess remarka-
ble regenerative properties. These properties enable them to repair damaged tissues
caused by degenerative diseases and restore the full functionality of organs and tis-
sues. Additionally, numerous stem cell types exhibit immunomodulatory, angio-
genic, and cell-protective properties, which could contribute to the restoration of
blood vessel integrity and tissue health [120,121].
It is important to note that the choice of therapy depends on the specific degenerative
disease, its stage, and individual patient factors. Treatment plans are typically developed
in consultation with healthcare professionals who can tailor interventions to the patient’s
needs. Additionally, a holistic approach that combines multiple strategies, including life-
style modifications and medication, is often the most effective way to address vascular
dysfunction and mitigate disease progression.

8. Future Directions and Research Opportunities

There are several gaps in our current understanding of the complex relationship be-
tween the vascular system and degenerative diseases, highlighting areas where further
research is needed:
i. Mechanisms of Vascular Dysfunction: While we know that vascular dysfunction is a
common feature in many degenerative diseases, the precise mechanisms underlying
this dysfunction remain incompletely understood. Elucidating the specific molecular
Int. J. Mol. Sci. 2024, 25, 2169 16 of 22

and cellular pathways involved in vascular damage and their crosstalk with degen-
erative disease pathology is crucial for developing targeted therapies.
ii. Biomarkers for Vascular Dysfunction: Identifying reliable biomarkers that can detect
early signs of vascular dysfunction and degenerative diseases is an ongoing challenge.
Research efforts are needed to discover and validate biomarkers that can predict the
risk of degenerative diseases and monitor vascular health.
iii. Interplay with Genetics: The influence of genetic factors on vascular dysfunction in
degenerative diseases is not fully understood. Further research is required to unravel
the genetic predispositions that may make some individuals more susceptible to vas-
cular complications.
iv. Role of the Microbiome: Emerging evidence suggests that the gut microbiome may
play a role in many degenerative diseases [122]. Investigating the interactions be-
tween gut microbiota and the vascular system in the context of a degenerative disease
could provide insights into novel therapeutic approaches.
v. Age-Related Changes: Aging is a significant risk factor for both degenerative diseases
and vascular dysfunction [16,17]. Research is needed to understand how age-related
changes in vessels and tissues interact with each other in the context of structural and
functional alterations that contribute to disease progression.
vi. Plasticity and Repair: A comprehensive understanding of the natural mechanisms for
repair and plasticity in the context of vessels and specific tissue is essential for a
deeper understanding of vascular dysfunction and degenerative disease [109]. Such
an understanding is pivotal for gaining deeper insights into vascular dysfunction and
degenerative diseases. Additional research is imperative in this field.
vii. Impact of Environmental Factors: The role of environmental factors, such as pollution,
diet, lifestyle, and climate change, in vascular dysfunction and degenerative diseases
needs further exploration [123]. Understanding how these factors interact with ge-
netic and biological mechanisms is vital.
viii. Long-Term Outcomes: Many studies focus on short-term outcomes of vascular inter-
ventions. There is a need for long-term follow-up to assess the durability and sus-
tained benefits of vascular-focused therapies in degenerative diseases.
ix. Integration of Data: Combining data from various sources, such as genomics, prote-
omics, and clinical records, can provide a comprehensive view of vascular dysfunc-
tion in degenerative diseases. Advanced data integration techniques and artificial in-
telligence can help uncover hidden patterns and relationships.
x. Ethnic and Racial Disparities: Investigating ethnic and racial disparities in the prev-
alence and impact of degenerative diseases and vascular dysfunction is essential for
addressing health inequities and tailoring treatments to diverse populations.
xi. Translational Research: Bridging the gap between basic science research and clinical
application is crucial. Further efforts are needed to translate promising laboratory
findings into effective treatments for patients with degenerative diseases.
In all, the complex relationship between the vascular system and degenerative dis-
eases is an area of ongoing research. Addressing these gaps in understanding will pave
the way for innovative strategies to prevent, diagnose, and treat these diseases, ultimately
improving the quality of life for affected individuals.

9. Concluding Remarks
Thus, it is evident that the vascular system is not merely a passive conduit for blood
flow but an active player in the pathogenesis and progression of various degenerative
conditions affecting multiple organ systems. Researchers and clinicians in the field of de-
generative disease should consider the pivotal role of vascular health as a potential thera-
peutic target and a key player in disease prevention. The insights gained from this review
underscore the urgent need for multidisciplinary collaboration and innovative ap-
proaches to tackle degenerative diseases comprehensively. Moreover, the integration of
Int. J. Mol. Sci. 2024, 25, 2169 17 of 22

vascular assessments and interventions into clinical practice becomes imperative. We

hope that this review will encourage continued exploration and further research in the
field and guide the development of precision medicine strategies that consider the vascu-
lar dimension in the management of degenerative diseases.

Funding:. This study did not receive any external funding, and supported by internal funding of
the Department of Laboratory Medicine and the department of Neurology.
Conflicts of Interest: All authors declare that there is no conflict of interest.

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