The vascular system is made up of blood vessels, such as arteries, veins, and capillaries (20). Blood vessels are organized in hierarchal levels with complex and different configurations designed to ensure efficient exchange of nutrients and waste in and between tissues throughout the body. Large arteries with diameters above 6 mm transport oxygenated blood from the heart to smaller arteries ranging between 1 and 6 mm in diameter, then to the arteriolar network with diameters of 100–1,000 μm, and last into capillary beds of 10–15 μm in diameter (21). The arterial wall is an organized structure composed of matrix proteins (collagen fibers oriented in various directions and elastic lamellae), vascular smooth muscle cells (VSMCs), and other matrix components, such as glycosaminoglycans and endothelial cells in the inner layer (22). The cross-sectional layers of the arterial wall are shown in Figure 1. The endothelium is a thin monolayer of simple squamous cells lining the inner surface of the whole cardiovascular system (23, 24). It was once thought to be just an inert layer wrapping all endovascular surfaces. However, over the last four decades, research on the endothelium has become enormous, and its results have led to an understanding of its complex functions (25). It forms a biocompatible barrier between the circulating blood and all the underlying tissues (26). The endothelium plays an essential role in vascular function through several mechanisms, including the synthesis and release of substances that act in an autocrine and/or paracrine form. It controls all cardiovascular activities by releasing several vasoactive agents (27). The endothelium-derived dilating and contracting factors are balanced under physiological conditions so that vascular homeostasis is maintained in favor of vasodilation. Dilatory factors include NO, hydrogen sulfide, prostacyclin (prostaglandin I2), and endothelium-derived hyperpolarizing factor, whereas contracting factors include endothelin, thromboxane, and asymmetric dimethyl arginine (ADMA) (27). Microcirculation is the terminal vascular network of the systemic circulation comprising microvessels with a diameter of <20 μm. These microvessels consist of arterioles, postcapillary venules, and capillaries. Microcirculation is regarded as the last destination of the cardiovascular system and is ultimately accountable for the transfer of oxygen from the red blood cells in the capillaries to the parenchymal cells where oxygen is delivered to fulfill the energy requirements of the tissue cells (28). The capillaries consist of a single layer of endothelial cells (29). The distensibility and elasticity of arteries keep a relatively fixed blood pressure regardless of the pulsating nature of blood flow by each heartbeat. Arteries expand as a result of receiving blood expelled from the heart during systolic contraction and eject it to the periphery during diastole to supply the peripheral circulation with a steady flow of blood during systole and diastole cycles (30). Some of the major vasoactive factors implicated in the vascular function of blood vessels are discussed below.

Vascular dysfunction comprises dysfunction of the endothelium (endothelial dysfunction), microvascular dysfunction, and large artery dysfunction due to arterial stiffness (9). Endothelial dysfunction is characterized by an imbalance between constrictive factors and dilatory factors, increased concentration of reactive oxygen species (ROS), pro-inflammatory factors, and decreased NO bioavailability (41). The production of NO depends on its precursor, L-arginine, which is synthesized in healthy humans from l-citrulline by endogenous synthesis. This means that reduced levels of L-arginine and l-citrulline contribute to NO insufficiency. Also, free radicals, such as superoxide (O₂^·), may react with NO to form peroxynitrite (ONOO⁻) radicals, thereby reducing NO levels (40). A variety of ROS-producing systems, such as NADPH oxidase, xanthine oxidase, eNOS, and enzymes of the mitochondrial respiratory chain, are found within the vascular wall. Moderate levels of ROS have important signaling roles under physiological conditions. Excessive and persistent production of ROS, however, when exceeding the present antioxidant defense enzymes, leads to oxidative stress and decreased NO production (53). It is documented that NO production can also be decreased by ADMA, which competes with the substrate of eNOS, L-arginine, thus inhibiting NO production (54). Endothelial NO is one of the major dilatory factors, and its insufficiency contributes to elevated vascular constriction (55). A study documents that deterioration of NO results in increased levels of ET-1, which is a major vasoconstrictor, leading to a decrease in endothelial dilatory capacity (56). A study conducted in South Africa finds that ADMA is inversely correlated with carotid intima-media thickness (57). Another study documents that black men and women have higher central systolic blood pressure, higher plasma ADMA, and lower urinary nitrate than their white counterparts. This suggests potential increased chances for vascular damage and large arterial stiffness in people of African ancestry in the future as a result of endothelial dysfunction (58).

Microvascular dysfunction is a condition characterized by impaired endothelium-dependent dilation of isolated arterioles. It is documented that microvascular dysfunction precedes and predicts the development of conduit artery atherosclerosis and its determinants (59). Abnormal microvascular function may occur as a result of structural alterations in small arteries due to inward eutrophic remodeling without overall growth of the cell, leading to decreased vasodilator reserves and changes in distensibility of arterioles (60). A study reports that remodeling (damage) of the small artery plays a crucial role in the increase of vascular resistance. This damage in the small arteries, characterized by the thickening of the carotid intima, may be considered as the first manifestation of target organ damage before it occurs in the large arteries (61). More direct impairment of microvascular function occurs as a result of persistent ischemia, manifesting as reduced maximal flow on computerized tomography without the presence of conduit stenosis (59). Microvascular dysfunction is linked to several conditions, such as smoking, obesity, hypertension, and diabetes (62). As such, microcirculatory alteration noted in the renal and retinal systems are extensively studied to investigate the predictive role of glycemic variations early in diabetes (60).

The loss of arterial elasticity, also called arterial stiffness, describes the mechanical property of artery resistance to deformation (63). The stability, compliance, and resilience of the vascular wall are dependent on the activity of two major scaffolding proteins, namely, elastin and collagen (64). The content of these proteins is usually made stable by a dynamic but slow process of their synthesis and degradation. Dysregulation of this balance between their production and degradation commonly stimulated by inflammatory molecules leads to the overproduction of collagen at abnormal levels, which diminishes the normal elastin content. This affects the elasticity and resistance of the arteries, contributing to vascular stiffness (63). With every heartbeat, a pulse wave generated by the arteries travels through the vascular bed until it reaches peripheral resistance or any bifurcation point, producing a new reflected wave back to the heart (65, 66). The reflected wave velocity and the stage of the cardiac cycle in which it happens (during systole or diastole) depends on the peripheral vascular resistance, elasticity primarily of the large arteries, and central blood pressure (66). In healthy individuals, arteries are compliant, and therefore, the reflected wave is slow and returns to the heart during the diastole cycle. However, in individuals with arterial stiffness, the reflected wave reaches the heart early during systole cycle. As a result, this increases the systolic blood pressure with a subsequent increase in cardiac workload to overcome the augmented systolic blood pressure (30, 66).

Vascular function constitutes endothelial function and functioning of the microcirculation and macrocirculation. Endothelial function is mostly assessed by flow mediated dilation (FMD) techniques, which require occlusion. Retinal imaging is mostly used to assess the functioning microcirculation, and the macrocirculation function can be assessed by measuring the pulse wave velocity (PWV) as discussed below (67, 68).

It is known that risk factors for CVDs begin early in life (5, 6). A study finds that carotid bifurcation regions depicted widespread intimal lipid accumulation among newborn cadavers (106). Moreover, bifurcation anatomy affects blood flow, which causes endothelial injury (106). This indicates that endothelial dysfunction begins early in life. A study confirms that offspring have a distinct endothelial regulatory micro RNA profile at birth, which is associated with altered endothelial cell behavior during the first 3 months of life (107). It is documented that maternal total cholesterol (TC) concentrations increase in human pregnancy to meet the demands of the growing fetus (108). In some pregnancies, however, TC increases excessively mainly due to low-density lipoprotein cholesterol levels, a condition called maternal supraphysiological hypercholesterolemia in pregnancy, which is associated with endothelial dysfunction of the umbilical vein and early development of atherosclerosis in the fetal aorta (109). Furthermore, endothelial dysfunction is associated with various obstetrical syndromes, such as fetal growth restriction (FGR) (110). Evidence shows that FGR fetuses alter their cardiovascular function in utero to adjust to persisting suboptimal conditions, mainly chronic hypoxia (111). Changes in cardiovascular function secondary to utero-placental deficiency may result in permanent alterations in vascular structure (112). Fetal growth restriction leads to low birth weight. Children born with low birth weight experience catch up growth during their first years of life, thus, accumulating greater visceral adiposity, exposing them to an adverse metabolic outcome (110). All these findings suggest that maternal cardiovascular risk factors may affect the vascular function of the fetus and neonates.

Obesity, a multifactorial condition characterized by excess adipose tissue is a major determinant of vascular dysfunction and constitutes a serious worldwide health problem (113). The adipose tissue, where fat is stored in the body, is a type of connective tissue comprising lipid-filled cells (adipocytes) surrounded by a matrix of collagen fibers, blood vessels, immune cells, and fibroblasts. It consists of several cells with adipocytes being the most abundant. Other cells include stromal vascular fraction (SVF), endothelial cells, macrophages, stem cells, fibroblasts, and lymphocytes (114). Persistent accumulation of fat in the adipose tissue leads to adipocyte hypertrophy and hyperplasia (113). Adipose tissue hypertrophy (adipocyte cell size increases) and hyperplasia (increase in adipocyte number) occurs in childhood (115). The expansion of adipocytes leads to an increased release of free fatty acids and necrotic cell death due to hypoxia and inflammation (116). During physiological conditions, inflammation is regarded as a protective mechanism. However, obesity is accompanied by some degree of inflammation called low-grade inflammation (117) whereby the adipose tissue secretes high levels of pro-inflammatory adipocytokines, including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), resistin, and leptin, due to cell death by necrosis following hypoxia (113). This causes an infiltration of neutrophils, eosinophils, monocytes, and lymphocytes to clean up the dead cells (117). The resident macrophages in the adipose tissue release chemo-attractants for macrophages, which results in the persistent nature of chronic inflammation. This, in turn, promotes the inhibition of the production of adiponectin, an anti-inflammatory adipokine (117). Adiponectin is regarded as a beneficial adipokine in relation to metabolism with plasma concentration indirectly associated with trunk obesity, type 2 diabetes risk, and insulin resistance, whereas leptin positively correlates with waist circumference and is associated with the onset of insulin resistance (95, 118). TNF-α is known to trigger insulin resistance in obese individuals. IL-6 is known to be implicated in the pathways of insulin sensitivity, lipoprotein lipase downregulation and triglyceride synthesis (119). Persistent release of these pro-inflammatory markers, such as TNF-α and IL-6 results in decreased production of adiponectin (120). Decreased plasma levels of adiponectin promote the synthesis of arginase, a metalloprotease that catalyzes the conversion of L-arginine to L-orthinine and urea. The increased concentrations of arginase compete with eNOS for the substrate L-arginine. Increased arginase activity uncouples eNOS for the synthesis of NO, thereby leading to reduced production of NO (121). A decreased bioavailability of NO leads to endothelial dysfunction. Defect in the synthesis of NO can also be caused by high concentrations of ADMA in the plasma (122). ADMA is an endogenous competitive inhibitor of L-arginine for all three isoforms of NOS. High levels of ADMA block the synthesis of NO and limit the cellular uptake of L-arginine, thereby further disrupting the production of NO. In this manner, ADMA further affects the endothelial function (123).

Secreted inflammatory molecules, including pro-inflammatory cytokines, contribute to the generation of ROS (124). Since adipose tissue are known to secrete pro-inflammatory cytokines, they may promote the generation of ROS. As such, adipose tissue is regarded as an independent factor for the development of oxidative stress (125). ROS are highly reactive radicals derived from molecular oxygen, such as O²⁻, hydrogen peroxide (H₂O₂), hydroxyl radical (OH·), and ONOO⁻, that impair structural conformation of protein, DNA, and RNA in the cell, resulting in cellular dysfunction and cell death (126). Under physiological conditions, ROS contribute to cellular growth regulation, differentiation, and apoptosis (114). Furthermore, they are produced from endothelial cells by several enzymes, including NADPH oxidases, xanthine oxidoreductase (XOR), and mitochondrial enzymes, among many other sources (127). It is known that H₂O₂ has vasodilatory effects, whereas O²⁻ is a vasoconstrictor and leads to endothelial dysfunction (128). High levels of O²⁻ may react with NO to form an unstable free radical called ONOO⁻ (129). Furthermore, ROS can be produced from the uncoupling of eNOS (129). eNOS uncoupling may occur due to limited availability of the substrate L-arginine (128). As a result, eNOS may produce O²⁻ instead of NO, leading to more defect in the synthesis of NO and, hence, endothelial dysfunction (129). Also, small, dense, low-density lipoprotein (LDL) in the lumen is deposited into the subendothelial space where it becomes oxidized by ROS to become ox-LDL, which activates endothelial cells, causing expressed receptors for white blood cells on the surface (130). It is reported that ox-LDL induces the expression of ICAM-1 and VCAM-1, increasing the adhesive properties of the endothelium. The production of NO by endothelial cells is inhibited by ox-LDL. It is documented that ox-LDL leads to oxidative stress, producing high amounts of O²⁻, which inactivates NO to form ONOO⁻ (131). The decrease in NO as a result of ox-LDL leads to endothelial dysfunction.

Although hypertension is generally known be a consequence of endothelial dysfunction (132, 133), recent data suggest that hypertension may be a cause of endothelial dysfunction. There are reports that hypertension-induced endothelial dysfunction may be a result of hypertension-induced oxidative and inflammation (134). Hypertension-associated oxidative stress regulated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria show reductions in endothelium-dependent vasodilation to acetylcholine in carotid arteries of mice exposed to increasing intraluminal pressure as a result of increase in NADPH oxidase activity and vascular O²⁻ production (135). Also, obese hypertensive rats with perivascular inflammation show impaired endothelial function (136). Further, the activation of the innate immunity complement pathway, which regulates inflammation, is negatively associated with vascular endothelial function in hypertensives (137). All these studies support the notion that hypertension may be the cause of endothelial dysfunction.

Endothelial dysfunction is a crucial risk factor for the development of high blood pressure as it not only impairs the control of the vascular tonus, but also alters structural function, such as the tunica intima of blood vessels (138). LDL as a result of hyperlipidemia, which is associated with obesity, may be deposited into the intima of blood vessels where they may be oxidized by ROS. This oxidized LDL (ox-LDL) activates the endothelial cells to induce monocyte recruitment into the endothelial wall (139). The recruited monocytes differentiate into macrophages that take up the ox-LDL via scavenger factors, resulting in intracellular lipid accumulation and subsequently the formation of foam cells (139, 140). Foam cells produce growth factors that cause the synthesis of collagen and VSMC to migrate into the intima, which begins to proliferate and secrete extracellular matrix, resulting in thickening of the arterial intima. Thickening of the intima can lead to severe CVDs, such as stroke, ischemic disease, and congestive heart failure later in life (139, 141).

It is known that early endothelial dysfunction decreases vascular relaxation and causes the infiltration of inflammatory cells, leading to mild inflammation in blood vessels (142). eNOS is formed in high concentrations in endothelial cells, specifically in the renal medulla, where it maintains medullary blood flow in response to renal vasoconstrictors, such as angiotensin II. Impaired activity of eNOS may be due to endothelial damage or extrinsic free radical activity altering NO activity (143). ROS may influence the effects of dilatory and constrictive factors, thus leading to elevated vascular resistance and acute kidney injury (144).

Sustained damage by hyperglycemia or other factors, such as hypertension in the microvessels of the retina results in diabetic retinopathy (145). Diabetic retinopathy is the main cause of blindness in high- and middle-income countries (109). Hyperglycemia increases hypoxia induced factor 1 (HIF-1) and insulin-like growth factor-1 (IGF-1). The overexpression of HIF-1 and IGF-1 and other factors activate Müller cells to transform into chronic inflammatory cells. Moreover, this induces overexpression and buildup of vascular endothelial growth factor (VEGF) causing fibroblast growth, thereby initiating fibrosis (146). VEGF is documented to stimulate angiogenesis and neovascularization, which are involved in the pathogenesis of proliferative retinopathy (145). Microvascular dysfunction can also result from arterial stiffness (147). Arterial stiffness is associated with normal and accelerated aging (147). The consequence of arterial stiffness includes augmented systolic blood pressure, which is characterized by pulse pressure (30, 148). Greater pulsatile pressure increases the pulsatile flow to penetrate deeper into the periphery and damage the microvasculature specifically in the brain and kidney (30).

The increasing prevalence of cardiovascular risk factors, such as hypertension, in SSA children has implications on their vascular health (4). However, very few studies assess the vascular function of children of African ancestry. A study in Kwa-Zulu Natal Province of South Africa shows that age and resting heart rate were positively associated with arterial stiffness among children aged 10–13 years old (149). Age could play an important role when assessing arterial stiffness (150). However, for a deeper understanding, it should be examined in conjunction with growth and maturation, given that body height at the transition from childhood to adolescence is documented to affect arterial stiffness. An association between resting heart rate and arterial stiffness in children is still lacking in the literature (149). A study conducted in the Eastern Cape Province, South Africa, among 6- to 9-year-old children finds that blood pressure parameters, such as mean arterial and diastolic blood pressure, increased with increasing PWV (151). This suggests that hypertension may result in vascular impairment in children. Another study conducted in Potchefstroom, North West Province of South Africa, in 6- to 8-year-old boys shows that oxidative stress is positively associated with cfPWV and carotid dorsalis pedis PWV in boys exposed to maternal cardiovascular risk compared with the non-maternal risk group (152). This suggests that oxidative stress may be an early mediator of vascular changes in children exposed to maternal cardiovascular risk. PWV significantly correlates with ADMA and systolic blood pressure (SBP) in a study conducted among 13- to 16-year-old children in the Eastern Cape Province of South Africa, suggesting that ADMA might be considered as a major risk factor of vascular dysfunction in adolescents (153). The PWV increased with cumulative time on ART in children living with HIV among primary school children in Cape Town, Western Cape Province of South Africa (154). In Mozambique, a study conducted among children with perinality-acquired HIV finds that PWV is higher in participants with increased visceral fat, elevated lipids, and insulin resistance (155). A study carried out in Egypt among 74 obese children aged 6–18 years finds a significant positive correlation between cIMT and BMI. cIMT equally shows a significant positive correlation with triglycerides and TC (156). Another study conducted in Egypt among 5- to 14-year-old children finds that cIMT is higher in obese children as compared with non-obese children. Further, obese children with elevated LDL and TC show increased risk for endothelial dysfunction and early signs of atherosclerosis (157). Thus, higher cIMT in obese children denotes increased risk for early vascular dysfunction. Exposure to risk factors of CVDs, such as hypertension and hyperlipidemia in obese children may induce alterations in the arteries, thus contributing to impaired endothelial function (156, 157). Higher PWV (carotid-radial, carotid-femoral, and carotid-dorsalis), diastolic blood pressure, and cIMT are reported in black boys than in white boys aged 6–8 years old in Potchefstroom, North West Province of South Africa. Moreover, black boys had increased levels of pentosidine, which is a biomarker for microvascular complications. However, arterial stiffness was not associated with pentosidine in both groups of boys, suggesting that vascular aging begins early in black population (158). Risk factors associated with vascular dysfunction in African children are summarized in Table 2.