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VASCULAR FUNCTION AND DYSFUNCTION
The cardiovascular system relies on functional blood vessels to transport nutrients, gases, and waste around the body. In a healthy cardiovascular system, arteries are highly compliant. This vascular compliance enables the propagation of the pressure wave along the arterial tree, which permits the maintenance of continuous blood flow across the capillaries (Glasser et al. 1997). Additionally, in a healthy cardiovascular system, vascular endothelial and smooth muscle cells function effectively to regulate vascular tone and blood flow (Nyberg, Gliemann, and Hellsten 2015). Vascular endothelial cells regulate vascular tone by producing vasoactive substances, while the vascular smooth muscle cells (VSMC) respond to the vascular dilating or constricting signals in order to achieve the correct contractile state (Nyberg, Gliemann, and Hellsten 2015). Vascular dysfunction, on the other hand, is characterized by a loss of vascular compliance (i.e. elevated arterial stiffness), and altered vascular tone, largely due to endothelial dysfunction (van Sloten 2017).
ascular function and dysfunction
THE ENDOTHELIUM IN NORMAL VASCULAR HOMEOSTASIS
The vascular endothelium is composed of a single layer of endothelial cells that lines the inner surface of the entire vasculature (Feletou, Huang, and Vanhoutte 2011) (Figure 1). In general, the primary functions of endothelial cells include the regulation of vascular tone, cellular adhesion, thromboresistance, VSMC proliferation, and vessel wall inflammation (Deanfield, Halcox, and Rabelink 2007). However, endothelial cells are heterogeneous, and their morphology and function varies widely depending on the type and location of the blood vessel within the vascular tree (dela Paz and D’Amore 2009). For example, leukocyte trafficking, which includes the attraction, rolling, firm adhesion, and infiltration of circulating leukocytes into the vascular tissue, takes place predominantly in post-capillary venules, although these steps can also be observed in large veins, capillaries, and arterioles (dela Paz and D’Amore 2009; Feletou, Huang, and Vanhoutte 2011). On the other hand, the regulation of vascular tone is an arterial function that primarily takes place at the level of the arterioles, as well as in the arteries (dela Paz and D’Amore 2009). Vascular tone refers to the level of vessel constriction in comparison to the maximal dilated state of the vessel, and is controlled by vasoactive compounds that stimulate the VSMCs to relax (vasodilators) or constrict (vasoconstrictors) the blood vessels (Sena, Pereira, and Seica 2013).
Vasodilators
Nitric oxide
In 1980 Furchgott and Zawadiski demonstrated for the first time that the endothelium was required for acetylcholine-mediated relaxation of isolated arteries (Furchgott and Zawadzki 1980). This seminal study led to the discovery of the most well characterized endothelium-derived vasodilator, nitric oxide (NO). NO is generated by nitric oxide synthases (NOS) located in endothelial tissue (eNOS) or neural tissue (nNOS), and from an inducible form of NOS referred to as iNOS.
Figure 2: Endothelial nitric oxide production, and its actions in the vascular smooth muscle cell. ACh= acetylcholine; BK= bradykinin; ATP= adenosine triphosphate; ADP= adenosine diphosphate; SP= substance P; SOCa 2+= store-operated Ca2+ channel; ER= endoplasmic reticulum; NO= nitric oxide; sGC= soluble guanylyl cyclase; cGMP= cyclic guanosine-3’, 5-monophosphate; MLCK= myosin light chain kinase Figure from Sandoo 2010 Open Cardiovascular Med J
In endothelial cells eNOS produces NO during the conversion of L-arginine to L-citrulline by endothelial nitric oxide synthase (eNOS) in the presence of co-factors, such as tetrahydropiopterin (BH4). When NO diffuses to the VSMC it activates soluble guanylate cyclase, resulting in cyclic guanosine-3,5-monophosphate (cGMP)-mediated relaxation of the VSMC (Deanfield, Halcox, and Rabelink 2007) eNOS include signaling molecules like bradykinin, adenosine, vascular endothelial growth factor and serotonin (Govers and Rabelink 2001). In addition to its role as a vasodilator, NO also exerts an anti-atherogenic effect by opposing leukocyte adhesion and migration, smooth muscle cell proliferation, platelet adhesion and aggregation, apoptosis, and inflammation (Sena, Pereira, and Seica 2013).
Vasodilatory prostaglandins
Prostaglandins are prostanoids derived from arachidonic acid, a 20-carbon unsaturated fatty acid, and generated by cyclooxygenase enzymes (Ricciotti and FitzGerald 2011). Two main isoforms of cyclooxygenase have been identified: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues, and generally helps to preserve homeostasis (Dubois et al. 1998). COX-2, on the other hand, is induced by inflammatory stimuli, and thus plays a more important role in prostaglandin formation during inflammation and in diseases, like cancer and hypertension (Dubois et al. 1998; Wong et al. 2010). Both COX-1 and COX-2 are expressed by endothelial cells, and to a lesser extent by VSMC (Feletou, Huang, and Vanhoutte 2011). The four principal bioactive prostaglandins generated in vivo are prostaglandin (PG) E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α). These molecules are involved in a multitude of physiological and pathological processes in almost all of the tissues in the body via the interaction with prostanoid receptors, which are classified into five subtypes (DP, EP, FP, IP and TP receptors) (Dubois et al. 1998; Feletou, Huang, and Vanhoutte 2011).
PGI2 is the major metabolite of arachadonic acid produced by the successive action of cyclooxygenase (COX-1 and COX-2 isoforms) and prostacyclin synthase in endothelial cells (Moncada and Vane 1978). Prostacyclin produces vasodilation by activating prostacyclin receptors on vascular smooth muscle, resulting in activation of adenylate cyclase, which increases cyclic adenosine monophosphate (cAMP) levels. This stimulates protein kinase A, ultimately resulting in VSMC relaxation (Lai et al. 2014). Prostacyclin production is stimulated by bradykinin, histamine, thrombin, serotonin, and shear stress (Shireman and Pearce 1996). Typically, the vasodilatory effects of prostacyclin are masked by other endothelium-derived vasodilators, and can only be observed when other pathways leading to endothelium-dependent vasodilation are inhibited (Feletou, Huang, and Vanhoutte 2011). However, prostacyclin appears to play an important role in maintaining vascular function in environments in which NO is limited in both animals and humans (Chataigneau et al. 1999; Feletou, Huang, and Vanhoutte 2011; Sun et al. 1999). For example, in people with cardiovascular diseases, COX-2 derived prostaglandin-mediated vasodilation can compensate for decreased NO bioavailability (Bulut et al. 2003; Szerafin et al. 2006). In addition to inducing vasodilation, prostacyclin also prevents platelet aggregation, and has anti-inflammatory and anti-thrombotic effects (Lai et al. 2014).
PGE2 is one of the most abundant prostaglandins, and exerts diverse effects on the body. For example PGE2 can produce both relaxation and contraction of vascular smooth muscle depending on the receptor with which it interacts (Feletou, Huang, and Vanhoutte 2011). PGE2 plays a critical role as a mediator of a variety of biological activities, including immune responses, gastrointestinal integrity, fertility, and blood pressure (Ricciotti and FitzGerald 2011). During inflammation, PGE2 contributes to the development of the classic signs of inflammation: redness, swelling, and pain (Funk 2001). Indeed, redness and swelling are a result of PGE2-mediated vasodilation, resulting in increased blood flow into inflamed tissues (Funk 2001). Furthermore, macrophages are known to generate PGE2, and their production of PGE2 increases in states of inflammation (Ricciotti and FitzGerald 2011). Additionally, endothelial cell-derived PGE2 can act as a potent vasodilator (Feletou, Huang, and Vanhoutte 2011). Although there is little evidence that PGE2 plays a role in endothelium-dependent vasodilation under normal conditions, some studies suggest that it could mediate vasodilation in inflammatory states (Feletou, Huang, and Vanhoutte 2011; Nguyen-Tu et al. 2018; Pelletier et al. 2012).
Endothelium-dependent vasodilation that is not mediated by NO or PGI2 is generally attributed to Endothelium derived hyperpolarizing factor (EDHF) (Feletou, Huang, and Vanhoutte 2011). The vasodilatory effect of EDHF becomes more important as vessel size decreases; therefore EDHF activity is most predominant in resistance vessels (Coats et al. 2001). Furthermore, EDHF-mediated vasodilation helps compensate for the loss of NO- and prostaglandin-mediated vasodilation in states in which NO is reduced, such as in aging and diabetes (Brandes et al. 2000; Gaubert et al. 2007; Scotland et al. 2005).
Vasoconstrictors
The endothelium also produces substances that cause vasoconstriction, such as endothelin, angiotensin II (ANGII), and vaso-constricting prostanoids like prostaglandin H2 (PGH2), PGF2α, and Thromboxane A2 (TXA2). Endothelin was originally identified as a potent endogenous vasoconstrictor, but is now known to exert a diverse set of actions in the vasculature. Three endothelin isoforms exist (ET-1, ET-2, and ET-3), of which ET-1 is the most frequently expressed (Rodriguez-Pascual et al. 2011; Shireman and Pearce 1996). The release of ET-1 can result in the activation of two different G-protein coupled receptors: endothelin receptor type A (ETAR) and endothelin receptor type B (ETBR) (Haynes and Webb 1998). The ETAR and ETBR expressed on VSMC mediate the sustained vasoconstriction response that is characteristic of the endothelins (Haynes and Webb 1998). On the other hand, activation of ETBR expressed on the endothelium mediates the release of endothelium-derived vasodilators, including NO, PGI2, and EDHF, as well as the rapid uptake of ET-1 (Haynes and Webb 1998). Therefore, the actions of the endothelial ETBR oppose the contracting vascular effects of the ETARs and ETBRs expressed on the VSMC. Acute blockade of ETAR receptor produces a small or no effect on mean arterial pressure, whereas blockade of ETBR results in increased mean arterial pressure (Pollock 2001; Pollock and Opgenorth 1993; Pollock and Pollock 2001). Therefore, evidence suggests that in healthy individuals ETBR plays a more important role in controlling basal blood pressure and vascular tone by protecting against the contracting effects of the endothelins.
In addition to its effects on vascular tone, endothelin can also act as a regulator of vascular remodeling, angiogenesis, and extracellular matrix synthesis (Rodriguez-Pascual et al. 2011). VSMC, cardiomyocytes, fibroblasts, and most notably endothelial cells express endothelin (Rodriguez-Pascual et al. 2011). The expression of endothelin is upregulated by TGF-β, TNF-α, the interleukins, insulin, and ANGII, and downregulated by NO, PGI2, hypoxia, and shear stress (Thorin and Webb 2010).
The cleavage of angiotensinogen via renin produces angiotensin I, which can be subsequently cleaved by angiotensin converting enzyme to produce ANGII. Two main ANGII receptors, AT1 and AT2, exist. The predominate vasoconstriction action of ANGII is mediated by AT1 expressed by the VSMC. This effect can be countered by the AT2 receptor, which causes vasodilation (Hernandez Schulman, Zhou, and Raij 2007).
Table of contents :
PART 1 – Forward
PART 2 – Review of the literature
I. VASCULAR FUNCTION AND DYSFUNCTION
A. THE ENDOTHELIUM IN NORMAL VASCULAR HOMEOSTASIS 30
1. Vasodilators
a. Nitric oxide
b. Vasodilatory prostaglandins
2. Vasoconstrictors
B. ENDOTHELIAL DYSFUNCTION: THE ROLE OF OXIDATIVE STRESS
1. Oxidative stress
a. Major sources of ROS in the vasculature
b. Antioxidants
i. Non-enzymatic antioxidants
ii. Enzymatic anti-oxidants
2. ROS and reduced NO bioavailability
a. NO degradation to peroxynitrite
b. Endothelial Nitric Oxide Synthase Uncoupling
C. INFLAMMATION AND VASCULAR DYSFUNCTION
1. The inflammatory response in the vasculature
2. Cytokines: major mediators of the immune response
3. Cytokine induced signaling and vascular reactivity
4. Oxidative stress and inflammation: sources of vascular dysfunction
II. TYPE 2 DIABETES
A. DIABETES: A GLOBAL HEALTH PROBLEM
1. Diabetes mellitus: a brief definition
2. The global burden of diabetes mellitus
B. PATHOPHYSIOLOGY OF TYPE 2 DIABETES
1. The interplay of genes and the environment in the development of T2D
2. Insulin resistance
3. β-cell dysfunction
4. Adipose tissue and inflammation
C. DIABETES MELLITUS AS A VASCULAR DISEASE
1. Evidence of vascular dysfunction in type 2 diabetes
a. Human studies
b. Animal studies
2. Microvascular complications
a. Retinopathy
b. Nephropathy
c. Neuropathy
3. Macrovascular complications
D. CAUSES OF VASCULAR DYSFUNCTION IN T2D
1. Hyperglycemia and vascular dysfunction
2. Insulin resistance
3. Free fatty acids
E. BLOOD RHEOLOGY IN TYPE 2 DIABETES
1. Blood rheology and its parameters: a brief summary
a. Whole blood viscosity
b. Red blood cell deformability
c. Red blood cell aggregation
2. Alterations in blood rheology related to type 2 diabetes
III. SICKLE CELL DISEASE AND SICKLE CELL TRAIT
A. SICKLE CELL DISEASE
1. Sickle cell disease and the hemoglobin molecule
2. Sickle cell anemia
3. Distribution and prevalence of the HbS mutation
B. PATHOPHYSIOLOGY OF SCA
1. HbS polymerization
2. Hemolytic anemia
3. Vaso-occlusive crises
4. Blood rheological profile in SCA
C. OXIDATIVE STRESS IN SCA
1. HbS auto-oxidation
2. Free plasma hemoglobin, heme, and iron
3. VOC ischemia-reperfusion: activation of XO
4. Inflammation
5. NO availability in SCD
a. Peroxynitrite formation
b. Hemolysis and NO bioavailability
D. SICKLE CELL TRAIT
1. Blood rheological abnormalities in SCT
2. Coagulation
3. Inflammation in SCT
4. Oxidative stress in SCT
5. Complications associated with SCT
a. Exercise-related Deaths
b. Renal Complications
c. Venous Thromboembolism
d. Stroke
e. Retinopathy
IV. COMBINED TYPE 2 DIABETES AND SICKLE CELL TRAIT
A. SCT and metabolic control
B. SCT and type 2 diabetes diagnosis
C. SCT and T2D-related complications
PART 3 – Personal Contributions
COMMENT: Sickle-cell trait and diagnosis of type 2 diabetes
STUDY 1: Evaluation of Agreement Between HbA1c, Fasting Glucose, and
Fructosamine in Senegalese Individuals with and without Sickle-cell Trait
STUDY 2: Increased prevalence of type 2 diabetes-related complications in
combined type 2 diabetes and sickle cell trait
STUDY 3: Altered blood rheology and impaired pressure-induced cutaneous
vasodilation in a mouse model of combined type 2 diabetes and sickle cell trait160
STUDY 4: Altered acetylcholine-mediated endothelium-dependent vasodilation invivo in a mouse model of combined type 2 diabetes and sickle cell trait
PART 4 – Conclusions and perspectives
PART 5 – References
PART 6 – Publications and communications
