**1. Introduction**

Vascular endothelium is considered as a largest endocrinal organ in the body, which has been shown to have a role in homeostasis in the body by exerting various functions [1]. It is made up of simple squamous epithelial cells that line blood vessels, lymphatic vessels, and the heart. The vascular endothelium has a total weight of about 1.5 kg. The endothelium has been recognized as a smart barrier and a key regulator of blood flow in micro- and macro-vascular circulation [2]. Endothelial function is very important, as it interacts with nearly every system in the body and selectively supplies nutrients and growth factors to every organ. On the other hand, endothelium also receives active metabolites and delivers them back to the

circulation. Previously, it was believed that, endothelium is an inactive barrier between blood and extravascular tissues. However, recent research has shown that the vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homeostasis.

## **2. Physiological function of endothelium**

When immediate surrounding tissues are at basal conditions, the endothelium functions to maintain the vessel homeostasis, which favors vessel dilatation over vasoconstriction [3]. The endothelium being a dynamic reactive tissue, responds to various intrinsic physical stimuli, that is, shear stress, temperature, and transmural pressure and external stimuli, that is, temperature, mental stress, neurohumoral responses, immune response, and medications [2, 4].

Under normal conditions, endothelial cell maintains basal perfusion, which is determined by cardiac output, systemic, and local vascular resistance. Endothelial metabolism, which is a key regulator of perfusion, is impaired during several disease states like infection, injury, aging, and inflammation [5]. Local blood flow is the result of vascular relaxation and contraction that is balanced by endotheliumderived vaso-dilatative and vaso-constrictive factors. Among these factors, one signal molecule stands out as hub and target of many pathways and mechanisms that is nitric oxide (NO) [6]. It is important to understand the biochemical foundations of NO for endothelial function. NO, a potent vasodilator, is released form the endothelium due to shear stress. This NO is released by endothelial nitric oxide synthase (eNOS) by utilizing L-arginine as a substrate, which leads to the production of intracellular cyclic GMP [7]. However, in an event when the NO-dependent vasodilator mechanism is compromised, then the cytochrome-derived factors, natriuretic peptide [8], and prostacyclin [9]-dependent vasodilator mechanism came in action.

During disease state, there is impaired endothelial function, and this results in the balance shift towards prevailing constrictive factors and/or down-regulation of vaso-dilatative factors. An important counterweight in the vascular balance is cyclooxygenase (COX). This mostly induces COX-1 which is endogenous and may involve COX-2 if it is induced. The COXs have a key role in generating vasoconstrictive factors.

The COX enzymes transform arachidonic acid into endoperoxides and further into thromboxane A2 (TXA2) [10], prostaglandins, and prostacyclin [11]. Local presence of thrombin evokes inducible NO release. Platelet release of serotonin and ADP in turn increases NO synthesis and release in healthy endothelium to induce dilatation [12]. When vasodilatory function of endothelium is impaired, then the thrombus formation is mechanically promoted by vasoconstriction via TXA2 and by the direct effect of serotonin on smooth muscle cells [13].

### **3. Endothelial dysfunction**

Traditionally, endothelial dysfunction has been associated to pathological conditions that have altered anticoagulant function, impaired anti-inflammatory properties of the endothelium, impaired modulation of vascular growth, and dysregulation of vascular remodeling. For instance, a plethora of studies have confirmed the impairment of endothelium-dependent vasorelaxation caused by a loss of NO bioactivity/availability in the vessel wall [4]. The loss of NO bioavailability

**93**

facilitate monocyte adhesion, a crucial step for plaque formation.

*Endothelial Dysfunction in Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.89365*

is the salient feature of a dysfunctional endothelium, which in turn is the sentinel of systemic or focal vascular disease. A number of previous studies have showed that most of the cardiovascular diseases were initiated from endothelial dysfunction. The decline in NO bioavailability may be caused by decreased expression of the endothelial cell eNOS [14], a lack of substrate or cofactors for eNOS [15], the presence of inhibitor of NOS [16], and alterations of cellular signaling, and finally, accelerated NO degradation by ROS [17]. Another aspect of endothelial dysfunction is impaired endothelial barrier function. Depending on the mode of pathophysiological change, this loss in barrier function may be localized or systemic. Localized loss of the selective barrier function (manifested as edema), coupled with the emigration of leukocytes, has been recognized as cardinal signs of inflammation [18]. From an immunological context, the body's primary reaction to tissue injury or infection is the leukocyte interacting with endothelium. However, from the perspective of hemostasis and thrombosis, endothelial dysfunction is characterized by activation of pro-inflammatory and pro-coagulant molecules, as well as the suppression of anti-inflammatory and anti-coagulant molecules. The intact and normal functioning endothelial lining provides a stable reservoir for blood as its luminal surface does not activate the coagulation cascade or promote leukocyteplatelet adhesion, and it also exhibits anticoagulant and fibrinolytic properties [19]. Systemic endothelial dysfunction may lead to widespread inflammation, vascular leakage, thrombocytopenia, and disseminated intravascular coagulation (DIC). On the other hand, localized endothelial dysfunction and leukocyte adhesion may lead to venous thrombosis. Other than altered endothelial barrier function, localized endothelial dysfunction also leads to tissue factor induction and increased von Willebrand factor (vWF) release that shifts the homeostatic balance towards the pro-coagulant-pro-inflammatory phenotype [20]. Intact endothelium release pro-fibrinolytic molecules like tissue plasminogen activator (TPA) [21]. Endothelial dysfunction suppressed TPA release, thereby impairing fibrinolytic function of endothelium [22]. In contrast to venous endothelial cells and microvascular endothelial cells, arterial endothelial cells are surrounded by a vascular smooth muscle layer and adventitial layer. Arterial endothelial cells physiologically experience high sheer stress and synthesize ample amount of NO that facilitate vascular relaxation. In the context of atherogenesis, endothelial cell dysfunction is mainly characterized by a loss of anatomical integrity of the intima, as described by the seminal *"Response-to-Injury Hypothesis"*. Endothelial cell injury and subsequent sub-endothelial matrix exposure lead to platelet adhesion and activation mediated through sub-endothelial collagen layer [23]. The initiating event in the atherogenic process is some form of overt injury to the intimal endothelial lining that is induced by noxious substances (e.g., oxidized cholesterol, cigarette smoke, hyperlipidemia, hypercholesterolemia, hyperglycemia, etc.) or altered hemodynamic sheer stress (e.g., abnormal blood flow caused by hypertension) [24]. In particular, local endothelial mechanical tearing was seen as the inciting stimulus for platelet adhesion, activation, and the localized release of platelet-derived growth factors. This would then elicit the migration, proliferation, and phenotypic modulation of medial smooth muscle cells and thus generate a fibromuscular plaque [25]. It is of great interest to establish the sequential event that leads to atherogenesis from endothelial injury. But, the direct link between endothelial injury and the genesis of atherosclerotic lesion is still unclear. However, the detailed morphologic examination in diet-induced fatty streak lesions in animal models failed to demonstrate unconcealed intimal injury or platelet adhesion. In this context, it is highly relevant that several molecules including high mobility group protein (HMGB-1) [26] and heat shock proteins (HSPs) [27] are released from injured endothelial cells and

#### *Endothelial Dysfunction in Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.89365*

*Basic and Clinical Understanding of Microcirculation*

**2. Physiological function of endothelium**

responses, immune response, and medications [2, 4].

homeostasis.

came in action.

tive factors.

circulation. Previously, it was believed that, endothelium is an inactive barrier between blood and extravascular tissues. However, recent research has shown that the vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular

When immediate surrounding tissues are at basal conditions, the endothelium functions to maintain the vessel homeostasis, which favors vessel dilatation over vasoconstriction [3]. The endothelium being a dynamic reactive tissue, responds to various intrinsic physical stimuli, that is, shear stress, temperature, and transmural pressure and external stimuli, that is, temperature, mental stress, neurohumoral

Under normal conditions, endothelial cell maintains basal perfusion, which is determined by cardiac output, systemic, and local vascular resistance. Endothelial metabolism, which is a key regulator of perfusion, is impaired during several disease states like infection, injury, aging, and inflammation [5]. Local blood flow is the result of vascular relaxation and contraction that is balanced by endotheliumderived vaso-dilatative and vaso-constrictive factors. Among these factors, one signal molecule stands out as hub and target of many pathways and mechanisms that is nitric oxide (NO) [6]. It is important to understand the biochemical foundations of NO for endothelial function. NO, a potent vasodilator, is released form the endothelium due to shear stress. This NO is released by endothelial nitric oxide synthase (eNOS) by utilizing L-arginine as a substrate, which leads to the production of intracellular cyclic GMP [7]. However, in an event when the NO-dependent vasodilator mechanism is compromised, then the cytochrome-derived factors, natriuretic peptide [8], and prostacyclin [9]-dependent vasodilator mechanism

During disease state, there is impaired endothelial function, and this results in the balance shift towards prevailing constrictive factors and/or down-regulation of vaso-dilatative factors. An important counterweight in the vascular balance is cyclooxygenase (COX). This mostly induces COX-1 which is endogenous and may involve COX-2 if it is induced. The COXs have a key role in generating vasoconstric-

The COX enzymes transform arachidonic acid into endoperoxides and further into thromboxane A2 (TXA2) [10], prostaglandins, and prostacyclin [11]. Local presence of thrombin evokes inducible NO release. Platelet release of serotonin and ADP in turn increases NO synthesis and release in healthy endothelium to induce dilatation [12]. When vasodilatory function of endothelium is impaired, then the thrombus formation is mechanically promoted by vasoconstriction via TXA2 and by

Traditionally, endothelial dysfunction has been associated to pathological conditions that have altered anticoagulant function, impaired anti-inflammatory properties of the endothelium, impaired modulation of vascular growth, and dysregulation of vascular remodeling. For instance, a plethora of studies have confirmed the impairment of endothelium-dependent vasorelaxation caused by a loss of NO bioactivity/availability in the vessel wall [4]. The loss of NO bioavailability

the direct effect of serotonin on smooth muscle cells [13].

**3. Endothelial dysfunction**

**92**

is the salient feature of a dysfunctional endothelium, which in turn is the sentinel of systemic or focal vascular disease. A number of previous studies have showed that most of the cardiovascular diseases were initiated from endothelial dysfunction. The decline in NO bioavailability may be caused by decreased expression of the endothelial cell eNOS [14], a lack of substrate or cofactors for eNOS [15], the presence of inhibitor of NOS [16], and alterations of cellular signaling, and finally, accelerated NO degradation by ROS [17]. Another aspect of endothelial dysfunction is impaired endothelial barrier function. Depending on the mode of pathophysiological change, this loss in barrier function may be localized or systemic. Localized loss of the selective barrier function (manifested as edema), coupled with the emigration of leukocytes, has been recognized as cardinal signs of inflammation [18]. From an immunological context, the body's primary reaction to tissue injury or infection is the leukocyte interacting with endothelium. However, from the perspective of hemostasis and thrombosis, endothelial dysfunction is characterized by activation of pro-inflammatory and pro-coagulant molecules, as well as the suppression of anti-inflammatory and anti-coagulant molecules. The intact and normal functioning endothelial lining provides a stable reservoir for blood as its luminal surface does not activate the coagulation cascade or promote leukocyteplatelet adhesion, and it also exhibits anticoagulant and fibrinolytic properties [19]. Systemic endothelial dysfunction may lead to widespread inflammation, vascular leakage, thrombocytopenia, and disseminated intravascular coagulation (DIC). On the other hand, localized endothelial dysfunction and leukocyte adhesion may lead to venous thrombosis. Other than altered endothelial barrier function, localized endothelial dysfunction also leads to tissue factor induction and increased von Willebrand factor (vWF) release that shifts the homeostatic balance towards the pro-coagulant-pro-inflammatory phenotype [20]. Intact endothelium release pro-fibrinolytic molecules like tissue plasminogen activator (TPA) [21]. Endothelial dysfunction suppressed TPA release, thereby impairing fibrinolytic function of endothelium [22]. In contrast to venous endothelial cells and microvascular endothelial cells, arterial endothelial cells are surrounded by a vascular smooth muscle layer and adventitial layer. Arterial endothelial cells physiologically experience high sheer stress and synthesize ample amount of NO that facilitate vascular relaxation. In the context of atherogenesis, endothelial cell dysfunction is mainly characterized by a loss of anatomical integrity of the intima, as described by the seminal *"Response-to-Injury Hypothesis"*. Endothelial cell injury and subsequent sub-endothelial matrix exposure lead to platelet adhesion and activation mediated through sub-endothelial collagen layer [23]. The initiating event in the atherogenic process is some form of overt injury to the intimal endothelial lining that is induced by noxious substances (e.g., oxidized cholesterol, cigarette smoke, hyperlipidemia, hypercholesterolemia, hyperglycemia, etc.) or altered hemodynamic sheer stress (e.g., abnormal blood flow caused by hypertension) [24]. In particular, local endothelial mechanical tearing was seen as the inciting stimulus for platelet adhesion, activation, and the localized release of platelet-derived growth factors. This would then elicit the migration, proliferation, and phenotypic modulation of medial smooth muscle cells and thus generate a fibromuscular plaque [25]. It is of great interest to establish the sequential event that leads to atherogenesis from endothelial injury. But, the direct link between endothelial injury and the genesis of atherosclerotic lesion is still unclear. However, the detailed morphologic examination in diet-induced fatty streak lesions in animal models failed to demonstrate unconcealed intimal injury or platelet adhesion. In this context, it is highly relevant that several molecules including high mobility group protein (HMGB-1) [26] and heat shock proteins (HSPs) [27] are released from injured endothelial cells and facilitate monocyte adhesion, a crucial step for plaque formation.
