Endothelium

Introduction

The vascular endothelium is a simple monolayer of cells that line the capillary lumen and is optimally placed at the interface of the blood circulation and vessel wall. Once considered to be merely a “cellophane wrapper” of the vessel wall, it is now well known that the endothelium is an active endocrine organ responsible for regulating vascular tone, blood coagulation and thrombosis, nutrient delivery, cellular adhesion, vascular smooth muscle cell proliferation, and inflammation, both in the brain and the periphery. The vascular endothelium in brain is unique since brain capillary endothelial cells lack fenestrations, are cemented together by extremely “tight junctions,” have minimal pinocytotic activity, and express enzymes capable of degradation of a number of molecules . The endothelial cells of the brain capillary are the anatomical site of the blood–brain barrier (BBB), a diffusional barrier formed by a complex network of the endothelial cells, pericytes, astrocytes, neurons, and the basement membrane that lines the brain capillary wall ( Fig. 8.1 ).

Besides the structural peculiarities of the brain vascular endothelium, certain functional characteristics of the brain vascular endothelium also contribute to brain-specific thrombosis and hemostasis . Antithrombotic molecule thrombomodulin and tissue plasminogen activator (tPA) are constitutively downregulated, whereas plasminogen activator inhibitor-1 (PAI-1) is upregulated, favoring an overall prothrombotic-antifibrinolytic environment at the brain capillary endothelium. Furthermore, vascular endothelial homeostasis is maintained by endothelium-derived vasoactive factors including nitric oxide (NO), prostaglandins, endothelium-derived hyperpolarizing factor (EDHF), endothelin-1, prostanoids, and angiotensin II.

Endothelial dysfunction is associated with ischemic stroke and other cerebrovascular diseases, and is characterized by altered vasodilation, inflammatory response, oxidative stress and vascular proliferation . In general, endothelial dysfunction implicates loss of any of the several functions of the endothelium; however, the most commonly observed dysfunction is related to loss of NO activity. The mechanisms involved in the pathogenesis of endothelial dysfunction are multifactorial and interwoven. For example, oxidative stress and reactive oxygen species (ROS) can disrupt the balance of NO, causing inflammation and damage the brain endothelium. This chapter will focus on the role of the cerebral endothelium, mechanisms involved in endothelial dysfunction, and strategies that can be used to protect brain endothelial function.

Endothelium and Vascular Tone

One of the main functions of the endothelium is to regulate vascular relaxation and contraction to maintain vascular tone by releasing endothelium-derived factors. Among the endothelium-derived factors, NO is central to the maintenance of vascular homeostasis. NO is produced from l -arginine by endothelial NO synthase (eNOS) and this gaseous signaling molecule diffuses to the vascular smooth muscle cells to activate guanylate cyclase. The resultant increase in cyclic guanosine monophosphate (cGMP) causes vasodilation and subsequent relaxation. The brain endothelium is exposed to NO produced by three different NOS enzymes: eNOS and nNOS (neuronal nitric oxide synthase) that are constitutively expressed, and iNOS (inducible nitric oxide synthase) that is induced under active inflammation. Besides NO, endothelium-derived hyperpolarizing factor is an important vasodilator in the cerebral circulation especially in small cerebral arteries during conditions of diminished NO. To maintain vasomotion, the endothelial cells also release powerful vasoconstrictors known as endothelium-derived contracting factors including endothelin-1, prostanoids including thromboxane A ₂ and prostaglandin H ₂ , and angiotensin II .

Endothelium and Thrombosis

The endothelium plays a crucial role in maintaining the balance between the pro- and anticoagulation systems of the vasculature. The endothelium exhibits heterogeneity in the expression of a number of antithrombotic factors, which assures adequate hemostasis in different tissues determined by local needs. Such tissue-specific thrombosis and hemostasis is particularly true for the cerebral endothelium. Thrombomodulin, a surface endothelial integral membrane protein, serves as a cofactor in the thrombin-induced activation of protein C anticoagulation pathway. Studies show low brain endothelial microvascular thrombomodulin expression. Furthermore, there is restricted expression of tPA, a serine-protease important for fibrin-mediated fibrinolysis, by brain microvascular endothelium. Moreover, studies show enhanced expression of PAI-1 and low expression of tissue factor pathway inhibitor by brain capillary endothelium. Overall, brain capillary endothelium exhibits low expression of most anticoagulant factors, thus shifting the balance toward a more prothrombotic state, which may be specifically important to prevent cerebral hemorrhages .