**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

a vasoconstrictive phenotype. Endothelial dysfunction is a condition comprising not only attenuated endothelium-dependent vasodilatation but also an augmented inflammatory endothelial activation that leads to vasoconstriction. Endothelial dysfunction contributes to hypertension, whereas hypertension also leads to endothelial dysfunction. In healthy endothelial tissues, a balance between endotheliumderived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs) is maintained. Endothelial dysfunction disturbs this balance. Several vasodilatory and vasoconstrictive factors regulate this balance. The endothelium secretes a number of vasodilator factors including NO. Generation of NO can activate guanylate cyclase (cGMP), which causes vasodilation through relaxation of vascular smooth muscle cells [56]. Another vasodilatory factor PGI2 secreted by the endothelium inhibits platelet aggregation and vascular smooth muscle cell proliferation [57]. Endothelial cells also secrete several vascular contracting factors including angiotensin-II (Ang-II), endothelin-I (ET-I), dinucleotide uridine adenosine tetraphosphate (UP4A), and COX-derived TXA2 [58]. Endothelins (ETs) are potent vasoconstrictor molecules having a key role in vascular homeostasis. Although there are three types of ET, vascular ECs mainly produce only ET-1, which has prominent roles in vasoconstriction. Active ET molecule is generated by the actions of an ET converting enzyme (ECE) found on the endothelial cell membranes. There are two basic types of ET-1 receptors: ET-A and ET-B, G-protein coupled receptors. Under normal conditions, the ET-A receptor is dominant in blood vessels [59]. ET-1 exerts vasoconstriction through activation of dihydropyridine channel or DHP channel or long lasting Ca++ channels (L-type) by binding to ET-A receptors on vascular smooth muscle cells. Smooth muscle cells expressed both ET-A and ET-B receptors. However, endothelial cells express only ET-B receptors, which negatively regulate NO release. Another vasorelaxation factor adenosine released from endothelial cells acts through purinergic receptor and maintains vascular perfusion [60]. Other than these factors, several cytokines and chemokines also play an important role in hypertension. Inflammatory cytokine induces generation of reactive oxygen species (ROS), one of the critical factors that link endothelial dysfunction and hypertension [61]. It is well established that Ang-II induces NADPH oxidases (NOX). But recent finding indicates additional source of ROS generation. In small subcutaneous arteries, a significant portion of Ang-II induced ROS is produced by COX-2. In the mouse aorta, the mitochondrial monoamine oxidase is another mediator of ROS generation and Ang-II or inflammation-induced endothelial dysfunction [62]. Therefore, mitochondrial monoamine oxidase-A and monoamine oxidase-B are also induced due to endothelial dysfunction in the vessels and generate a significant amount of H2O2 sufficient to quench endothelial NO. In spite of that, other mitochondrial ROS generating systems, that is, p66Shc, also contribute to hypertensioninduced ROS production. ROS production is also regulated by several intracellular signaling, which further attenuate endothelial dysfunction and hypertension.

### **6. Endothelial dysfunction in heart failure**

Heart failure (HF) is the most common cause of hospitalization in cardiovascular disease with a high mortality rate. Despite novel treatment options for patients suffering from HF, morbidity and mortality rates are still high. The impact of the growing HF on global public health is a great concern in health care research. With the advancement of medical management, survival of acute coronary disease and cardiac ischemia has been improved. However, in myocardial infarction, prognosis is still poor, as HF with preserved ejection fraction (HFpEF) has a 65% mortality rate at 5 years. While the heart as the failing "pumping" organ was an initial

**97**

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

focus in research and treatment, neurohumoral activation and subsequently the role of a failing endothelium were recognized and investigated in recent years. Traditionally, HF was recognized as impairment of cardiac muscle activity, known as cardiomyopathy. Later, it was found that altered perfusion in cardiac arteries due to atherogenesis also contributes to cardiac ischemia that leads to cardiomyopathy. Reduced myocardial perfusion due to impaired ventricular function is at least in part a consequence of reduced endothelium-dependent vasodilator capacity of coronary arteries. The prominent regulatory activity of the vascular endothelium in HF was discovered about two decades ago, and its assessment in different cardiovascular disorders, including HF, has been the focus of intense research [63]. On the other hand, declined peripheral vasodilation causes higher systemic and pulmonary vascular resistance and together with stiffness of conductance arteries leads to increased afterload. Elevated afterload further increases cardiac workload and therefore worsens myocardial function. The decreased exercise capability is aggravated by vasomotor dysfunction of the skeletal muscle vessel by increases vascular resistance. Altered endothelial metabolism further contributes to increasing cardiac afterload [13]. Indeed, various aspects of endothelial function are affected in heart failure, including vasomotor, hemostatic, antioxidant, and anti-inflammatory activities [63, 64]. Differences also exist in the pattern of endothelial dysfunction depending on etiology, severity, and stability of HF in individual patients. Endothelial dysfunction also plays a central role in HF. The failing heart is characterized by an altered redox state with overproduction of ROS. The increasing evidence suggests that the abnormal cardiac and vascular phenotypes characterizing the failing heart are caused in large part by imbalances between NO bioavailability and oxidative stress [65]. During initial stages of HF, inflammatory mediators from the myocardium and altered local shear forces modulate gene expression, leukocyte infiltration, increased cytokine production, increased ROS generation, and diminished NO bioavailability. Clinical studies showed significant up-regulation of plasma markers of endothelial activation (e.g. E-selectin) and endothelial damage (e.g. vWF) in HF [22, 63]. However, it is difficult to determine if endothelial dysfunction is the cause or effect of the HF. Therefore, HF is regarded as thrombotic complication. As mentioned earlier, during atherogenesis, decreased lumen of cardiac arteries leads to reduced perfusion to the heart muscle. This phenomenon is coupled with increased sheer stress and impaired blood flow. This reduced perfusion either led to ischemia–reperfusion injury or coronary artery thrombosis [63]. Studies showed that endothelial dysfunction is one of the principle mediators of ischemia–reperfusion injury and thrombosis. This explains the increased endothe-

lial dysfunction markers in coronary artery disease, HF, and thrombosis.

subdivided into acute ischemic stroke and hemorrhagic stroke [66]. Acute ischemic stroke is among the leading causes of death and long-term disability. Cerebrovascular stroke in small vessel has functional (lacunar stroke, cognitive impairment, gait, and movement disorders) and structural (small subcortical infarct, lacunar infarct, lacunes, white matter lesions, and micro bleeds) consequences. In the past few decades, the immense development of neuro-radiological methods enabled better imaging of cerebral blood vessels. From the clinical point of view, it is very important to identify the location of vascular lesion. However,

The global burden of neurological diseases including cerebrovascular stroke has significantly increased, and development of new treatment modalities for cerebrovascular diseases is an urgent need. Cerebrovascular stroke can be broadly

**7. Endothelial dysfunction in stroke**

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

*Basic and Clinical Understanding of Microcirculation*

**6. Endothelial dysfunction in heart failure**

Heart failure (HF) is the most common cause of hospitalization in cardiovascular disease with a high mortality rate. Despite novel treatment options for patients suffering from HF, morbidity and mortality rates are still high. The impact of the growing HF on global public health is a great concern in health care research. With the advancement of medical management, survival of acute coronary disease and cardiac ischemia has been improved. However, in myocardial infarction, prognosis is still poor, as HF with preserved ejection fraction (HFpEF) has a 65% mortality rate at 5 years. While the heart as the failing "pumping" organ was an initial

a vasoconstrictive phenotype. Endothelial dysfunction is a condition comprising not only attenuated endothelium-dependent vasodilatation but also an augmented inflammatory endothelial activation that leads to vasoconstriction. Endothelial dysfunction contributes to hypertension, whereas hypertension also leads to endothelial dysfunction. In healthy endothelial tissues, a balance between endotheliumderived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs) is maintained. Endothelial dysfunction disturbs this balance. Several vasodilatory and vasoconstrictive factors regulate this balance. The endothelium secretes a number of vasodilator factors including NO. Generation of NO can activate guanylate cyclase (cGMP), which causes vasodilation through relaxation of vascular smooth muscle cells [56]. Another vasodilatory factor PGI2 secreted by the endothelium inhibits platelet aggregation and vascular smooth muscle cell proliferation [57]. Endothelial cells also secrete several vascular contracting factors including angiotensin-II (Ang-II), endothelin-I (ET-I), dinucleotide uridine adenosine tetraphosphate (UP4A), and COX-derived TXA2 [58]. Endothelins (ETs) are potent vasoconstrictor molecules having a key role in vascular homeostasis. Although there are three types of ET, vascular ECs mainly produce only ET-1, which has prominent roles in vasoconstriction. Active ET molecule is generated by the actions of an ET converting enzyme (ECE) found on the endothelial cell membranes. There are two basic types of ET-1 receptors: ET-A and ET-B, G-protein coupled receptors. Under normal conditions, the ET-A receptor is dominant in blood vessels [59]. ET-1 exerts vasoconstriction through activation of dihydropyridine channel or DHP channel or long lasting Ca++ channels (L-type) by binding to ET-A receptors on vascular smooth muscle cells. Smooth muscle cells expressed both ET-A and ET-B receptors. However, endothelial cells express only ET-B receptors, which negatively regulate NO release. Another vasorelaxation factor adenosine released from endothelial cells acts through purinergic receptor and maintains vascular perfusion [60]. Other than these factors, several cytokines and chemokines also play an important role in hypertension. Inflammatory cytokine induces generation of reactive oxygen species (ROS), one of the critical factors that link endothelial dysfunction and hypertension [61]. It is well established that Ang-II induces NADPH oxidases (NOX). But recent finding indicates additional source of ROS generation. In small subcutaneous arteries, a significant portion of Ang-II induced ROS is produced by COX-2. In the mouse aorta, the mitochondrial monoamine oxidase is another mediator of ROS generation and Ang-II or inflammation-induced endothelial dysfunction [62]. Therefore, mitochondrial monoamine oxidase-A and monoamine oxidase-B are also induced due to endothelial dysfunction in the vessels and generate a significant amount of H2O2 sufficient to quench endothelial NO. In spite of that, other mitochondrial ROS generating systems, that is, p66Shc, also contribute to hypertensioninduced ROS production. ROS production is also regulated by several intracellular signaling, which further attenuate endothelial dysfunction and hypertension.

**96**

focus in research and treatment, neurohumoral activation and subsequently the role of a failing endothelium were recognized and investigated in recent years. Traditionally, HF was recognized as impairment of cardiac muscle activity, known as cardiomyopathy. Later, it was found that altered perfusion in cardiac arteries due to atherogenesis also contributes to cardiac ischemia that leads to cardiomyopathy. Reduced myocardial perfusion due to impaired ventricular function is at least in part a consequence of reduced endothelium-dependent vasodilator capacity of coronary arteries. The prominent regulatory activity of the vascular endothelium in HF was discovered about two decades ago, and its assessment in different cardiovascular disorders, including HF, has been the focus of intense research [63]. On the other hand, declined peripheral vasodilation causes higher systemic and pulmonary vascular resistance and together with stiffness of conductance arteries leads to increased afterload. Elevated afterload further increases cardiac workload and therefore worsens myocardial function. The decreased exercise capability is aggravated by vasomotor dysfunction of the skeletal muscle vessel by increases vascular resistance. Altered endothelial metabolism further contributes to increasing cardiac afterload [13]. Indeed, various aspects of endothelial function are affected in heart failure, including vasomotor, hemostatic, antioxidant, and anti-inflammatory activities [63, 64]. Differences also exist in the pattern of endothelial dysfunction depending on etiology, severity, and stability of HF in individual patients. Endothelial dysfunction also plays a central role in HF. The failing heart is characterized by an altered redox state with overproduction of ROS. The increasing evidence suggests that the abnormal cardiac and vascular phenotypes characterizing the failing heart are caused in large part by imbalances between NO bioavailability and oxidative stress [65]. During initial stages of HF, inflammatory mediators from the myocardium and altered local shear forces modulate gene expression, leukocyte infiltration, increased cytokine production, increased ROS generation, and diminished NO bioavailability. Clinical studies showed significant up-regulation of plasma markers of endothelial activation (e.g. E-selectin) and endothelial damage (e.g. vWF) in HF [22, 63]. However, it is difficult to determine if endothelial dysfunction is the cause or effect of the HF. Therefore, HF is regarded as thrombotic complication. As mentioned earlier, during atherogenesis, decreased lumen of cardiac arteries leads to reduced perfusion to the heart muscle. This phenomenon is coupled with increased sheer stress and impaired blood flow. This reduced perfusion either led to ischemia–reperfusion injury or coronary artery thrombosis [63]. Studies showed that endothelial dysfunction is one of the principle mediators of ischemia–reperfusion injury and thrombosis. This explains the increased endothelial dysfunction markers in coronary artery disease, HF, and thrombosis.
