**4. Endothelial dysfunction in atherosclerosis**

Endothelial dysfunction of lesion-prone areas of the arterial vasculature leads to atherosclerotic plaque formation [28]. Sequential deterioration of arterial vasculature along with increased sheer stress contributes to lesion formation. Endothelial dysfunction is one of the early events that are responsible for the deterioration of arterial vasculature [29]. Recent insight into the cellular mechanisms involved in atherogenesis shows that deleterious modifications of endothelial physiology or metabolism is the initial event of vascular remodeling that represents a crucial step in the development of atherosclerosis and are also involved in the development of plaque and the occurrence of atherosclerosis [2]. The sequential event including focal permeation, trapping, and physicochemical modification of circulating lipoprotein particles in the sub-endothelial space constructs an inflammatory lesion [30]. This initiates a coordinated cellular signaling, followed by complex pathogenic sequence and endothelial activation. Activated endothelial cells express several cell adhesion molecules, which facilitate selective recruitment of circulating monocytes from the blood, and invade the tunica intima, where they differentiate into macrophages. These macrophages also abnormally take up modified lipoproteins to become foam cells (the hallmark of early fatty streak lesions) [31, 32]. The activated endothelium and macrophages release multiple chemokine and growth factors which act on neighboring smooth muscle cells (or precursors cell) [33] to induce their proliferation and synthesis of extracellular matrix components within the intimal compartment, thus generating a fibromuscular plaque34. This progressive structural remodeling of developing lesions results in the formation of a fibrous cap, overlying a lipid-rich necrotic core that consists of oxidized lipoproteins, cholesterol crystals, and cellular debris. This is also accompanied by varying degrees of matrix remodeling and calcification [34, 35]. The lateral edges of these complicated plaques also contain a rich population of inflammatory cells, that is, activated macrophages, T-lymphocyte, and dendritic cells [36], which secrete several cytokines and chemokines that further activate endothelial pro-inflammatory phenotype and contribute to structural instability of the plaque through release of proteolytic enzymes (matrix metalloproteases) that lead to modification of sub-endothelial matrix components [37]. Another aspect of atherogenesis is governed by lipoproteins, mainly low-density lipoproteins (LDL). This initial arterial remodeling through accumulation of lipids is known as fatty streak formation. The first changes in the arterial wall occur at the branch points of arteries, where adaptive intimal thickening occurs in response to normal hemodynamic stresses [38]. During the early stage of atherogenesis, LDL particles leave the blood and enter the arterial intima, composed of endothelial cells. Fat droplets (LDL) may also accumulate in the cytoplasm of vascular smooth muscle cells (VSMCs) [35]. LDL particles are then modified by enzymes and are oxidized into a highly reactive pro-inflammatory molecule (oxidized LDL), that is recognized by pattern recognition receptors, that is, Toll-like receptors (TLRs) present in endothelial cells as well as pro-inflammatory macrophages [39]. Oxidized LDL incites the reaction of the innate inflammatory system within the intima and contributes to vascular remodeling. Inflammation begins when activated endothelial cells (through TLRs) express cell adhesion molecules and VSMCs secrete chemokines and chemoattractants, which together draw monocytes, lymphocytes, mast cells, and neutrophils into the arterial wall [40]. Once monocytes enter into the arterial wall through the intima, they become activated into macrophages. These macrophages take up lipids as multiple small inclusions and become transferred into foam cells [41]. The degree of lipid accumulation is critical for early stage diagnosis of atherosclerosis. Atherosclerosis is believed to start when the lipid accumulation appears as confluent

**95**

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

**5. Endothelial dysfunction in hypertension**

Hypertension affects significantly to worldwide cardiovascular morbidity and mortality and is considered as a diagnostic factor for cardiovascular disease. Hypertension appears to have a complex association with endothelial dysfunction, a phenotypical alteration of the vascular endothelium that precedes the development of adverse cardiovascular events. Endothelial cells along with the vascular smooth muscle cells of resistance vessels (arteries and arterioles) regulate hypertension [54] as they continuously constrict and dilate according to the rhythm of cardiac cycle. In response to the blood flow (perfusion), the quiescent healthy endothelium continuously releases potent vasodilators, which have the potential to lower vascular resistance, thereby regulating the blood pressure [55]. In normal condition, basal perfusion is determined by cardiac output, systemic, and local resistance. In an intact healthy vessel, endothelial cell always maintains a vasodilatory rather than

extracellular lipid pools and extracellular lipid cores with and decreased cellularity [42]. Endothelial cell dysfunction is also responsible for VSMC proliferation and differentiation to myofibroblast. In an intact vessel, VSMCs never come into contact with plasma proteins and are therefore devoid of growth factor present in plasma. In physiological conditions, VSMCs are always maintained in quiescent states. During early inflammation and endothelial cell activation, VSMCs receive signal from dying cells or growth factors that modify VSMCs to myofibroblast (more proliferative counterpart). Altered VSMCs (myofibroblast) also secrete proteoglycans, collagen, and elastic fibers into the sub-endothelial matrix [43]. This transformation of VSMCs further worsens the histological structure and leads to formation of thin-cap fibroatheroma formation [44]. Fibroatheroma can be of two different types depending on the content and stability of the plaque. Stability of the plaque also determines the fate of the fibroatheroma. Unstable fibroatheroma leads to thrombotic plaque formation, whereas stable fibroatheroma accumulates calcium, becomes stiff, and eventually leads to occlusion [44, 45]. Unstable or vulnerable plaques may lead to a catastrophic transition into atherosclerotic lesion—frank plaque rupture, with luminal release of the highly thrombogenic contents [46, 47]. Else, some significant clinical sequelae can be seen from superficial intimal erosions, without any indication of plaque rupture [48]. Therefore, lately an acute transition appears leading to endothelial cell apoptosis, with localized endothelial denudation and thrombus formation leading to obstruction in regional blood flow [49, 50], whereas the stable lesions, having thick fibrous cap and less lipid as well as inflammatory cell content, can gradually invade on the lumen of the vessel causing ischemic symptoms without atherothrombotic events [51, 52]. Many ruptures of thin fibrous caps are clinically silent in that they heal by forming fibrous tissue matrices of cells, collagen fibers, and extracellular space but may rupture again with thrombus formation of the necrotic core, triggering an atherothrombotic occlusion. These cyclic changes of rupture, thrombosis, and healing may recur as many as four times at a single site in the arterial wall, resulting in multiple layers of healed tissue. In all these steps, calcium deposition in the wall of the vessels forms small aggregates initially, which turns into large nodules at later stage. In later stage, these plaques may rupture and expose the nodules, and it became sites for thrombus formation [47]. Therefore, the increasing number of plaques itself might become adequate to form significant stenosis, which may cause a shattering ischemic event due to flow restriction [53]. Based on its multiple regulatory roles throughout this complex series of events, it is evident that endothelial dysfunction constitutes a well-coordinated multicellular pathogenic sequence that leads to atherosclerosis.

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

*Basic and Clinical Understanding of Microcirculation*

**4. Endothelial dysfunction in atherosclerosis**

Endothelial dysfunction of lesion-prone areas of the arterial vasculature leads to atherosclerotic plaque formation [28]. Sequential deterioration of arterial vasculature along with increased sheer stress contributes to lesion formation. Endothelial dysfunction is one of the early events that are responsible for the deterioration of arterial vasculature [29]. Recent insight into the cellular mechanisms involved in atherogenesis shows that deleterious modifications of endothelial physiology or metabolism is the initial event of vascular remodeling that represents a crucial step in the development of atherosclerosis and are also involved in the development of plaque and the occurrence of atherosclerosis [2]. The sequential event including focal permeation, trapping, and physicochemical modification of circulating lipoprotein particles in the sub-endothelial space constructs an inflammatory lesion [30]. This initiates a coordinated cellular signaling, followed by complex pathogenic sequence and endothelial activation. Activated endothelial cells express several cell adhesion molecules, which facilitate selective recruitment of circulating monocytes from the blood, and invade the tunica intima, where they differentiate into macrophages. These macrophages also abnormally take up modified lipoproteins to become foam cells (the hallmark of early fatty streak lesions) [31, 32]. The activated endothelium and macrophages release multiple chemokine and growth factors which act on neighboring smooth muscle cells (or precursors cell) [33] to induce their proliferation and synthesis of extracellular matrix components within the intimal compartment, thus generating a fibromuscular plaque34. This progressive structural remodeling of developing lesions results in the formation of a fibrous cap, overlying a lipid-rich necrotic core that consists of oxidized lipoproteins, cholesterol crystals, and cellular debris. This is also accompanied by varying degrees of matrix remodeling and calcification [34, 35]. The lateral edges of these complicated plaques also contain a rich population of inflammatory cells, that is, activated macrophages, T-lymphocyte, and dendritic cells [36], which secrete several cytokines and chemokines that further activate endothelial pro-inflammatory phenotype and contribute to structural instability of the plaque through release of proteolytic enzymes (matrix metalloproteases) that lead to modification of sub-endothelial matrix components [37]. Another aspect of atherogenesis is governed by lipoproteins, mainly low-density lipoproteins (LDL). This initial arterial remodeling through accumulation of lipids is known as fatty streak formation. The first changes in the arterial wall occur at the branch points of arteries, where adaptive intimal thickening occurs in response to normal hemodynamic stresses [38]. During the early stage of atherogenesis, LDL particles leave the blood and enter the arterial intima, composed of endothelial cells. Fat droplets (LDL) may also accumulate in the cytoplasm of vascular smooth muscle cells (VSMCs) [35]. LDL particles are then modified by enzymes and are oxidized into a highly reactive pro-inflammatory molecule (oxidized LDL), that is recognized by pattern recognition receptors, that is, Toll-like receptors (TLRs) present in endothelial cells as well as pro-inflammatory macrophages [39]. Oxidized LDL incites the reaction of the innate inflammatory system within the intima and contributes to vascular remodeling. Inflammation begins when activated endothelial cells (through TLRs) express cell adhesion molecules and VSMCs secrete chemokines and chemoattractants, which together draw monocytes, lymphocytes, mast cells, and neutrophils into the arterial wall [40]. Once monocytes enter into the arterial wall through the intima, they become activated into macrophages. These macrophages take up lipids as multiple small inclusions and become transferred into foam cells [41]. The degree of lipid accumulation is critical for early stage diagnosis of atherosclerosis. Atherosclerosis is believed to start when the lipid accumulation appears as confluent

**94**

extracellular lipid pools and extracellular lipid cores with and decreased cellularity [42]. Endothelial cell dysfunction is also responsible for VSMC proliferation and differentiation to myofibroblast. In an intact vessel, VSMCs never come into contact with plasma proteins and are therefore devoid of growth factor present in plasma. In physiological conditions, VSMCs are always maintained in quiescent states. During early inflammation and endothelial cell activation, VSMCs receive signal from dying cells or growth factors that modify VSMCs to myofibroblast (more proliferative counterpart). Altered VSMCs (myofibroblast) also secrete proteoglycans, collagen, and elastic fibers into the sub-endothelial matrix [43]. This transformation of VSMCs further worsens the histological structure and leads to formation of thin-cap fibroatheroma formation [44]. Fibroatheroma can be of two different types depending on the content and stability of the plaque. Stability of the plaque also determines the fate of the fibroatheroma. Unstable fibroatheroma leads to thrombotic plaque formation, whereas stable fibroatheroma accumulates calcium, becomes stiff, and eventually leads to occlusion [44, 45]. Unstable or vulnerable plaques may lead to a catastrophic transition into atherosclerotic lesion—frank plaque rupture, with luminal release of the highly thrombogenic contents [46, 47]. Else, some significant clinical sequelae can be seen from superficial intimal erosions, without any indication of plaque rupture [48]. Therefore, lately an acute transition appears leading to endothelial cell apoptosis, with localized endothelial denudation and thrombus formation leading to obstruction in regional blood flow [49, 50], whereas the stable lesions, having thick fibrous cap and less lipid as well as inflammatory cell content, can gradually invade on the lumen of the vessel causing ischemic symptoms without atherothrombotic events [51, 52]. Many ruptures of thin fibrous caps are clinically silent in that they heal by forming fibrous tissue matrices of cells, collagen fibers, and extracellular space but may rupture again with thrombus formation of the necrotic core, triggering an atherothrombotic occlusion. These cyclic changes of rupture, thrombosis, and healing may recur as many as four times at a single site in the arterial wall, resulting in multiple layers of healed tissue. In all these steps, calcium deposition in the wall of the vessels forms small aggregates initially, which turns into large nodules at later stage. In later stage, these plaques may rupture and expose the nodules, and it became sites for thrombus formation [47]. Therefore, the increasing number of plaques itself might become adequate to form significant stenosis, which may cause a shattering ischemic event due to flow restriction [53]. Based on its multiple regulatory roles throughout this complex series of events, it is evident that endothelial dysfunction constitutes a well-coordinated multicellular pathogenic sequence that leads to atherosclerosis.
