Diverse pathologic processes contribute to common vascular diseases such as atherosclerosis and hypertension. During the past 2 decades, these pathologic events have been defined with increasing clarity at a cellular and molecular level, and strategies are emerging to treat these primary processes rather than simply treating the secondary manifestations of vascular disease. For this reason, understanding normal functions of vascular cells and how they are altered by various vascular insults has become essential for both basic investigators and clinicians caring for patients with peripheral vascular disease, coronary artery disease, and hypertension. This chapter introduces important concepts in vascular biology and emphasizes how fundamental aspects of vascular control are altered in common disease conditions.
Normal endothelial cell function is crucial to homeostasis in the vascular system. During the past 30 years, it has become apparent that diseases such as atherosclerosis are ultimately manifestations of endothelial dysfunction. Normally, the endothelium has three major roles: (1) it is a metabolically active secretory tissue; (2) it serves as an anticoagulant, antithrombotic surface; and (3) it provides a barrier to the indiscriminate passage of blood constituents into the arterial wall. The implications of these physiologic properties for vascular biology are considered separately.
Endothelial Cell Metabolism and Secretion of Vasoactive Factors
Endothelial cells secrete vasoactive substances that play a major role in the control of vascular tone. These molecules include vasodilators such as prostacyclin, nitric oxide (NO), and endothelial-derived hyperpolarizing factors (EDHFs) such as hydrogen peroxide and eicosanoids.1-3 In addition, the endothelium produces vasoconstrictor substances, including endothelin4 and vasoconstrictor prostanoids.5
Endothelial cells also manufacture and secrete substances such as factor VIII antigen, von Willebrand factor, tissue factor, thrombomodulin, and tissue plasminogen activator (tPA), which are all involved in coagulation/fibrinolytic pathways. Structural components of the extracellular matrix (ECM) synthesized by these cells include collagen, elastin, glycosaminoglycans, and fibronectin.6,7 The composition of the ECM is dynamically modulated by matrix metalloproteinases (MMPs), enzymes that degrade matrix protein and participate in its remodeling. These enzymes are secreted by both endothelial and smooth muscle cells (SMCs).8,9 In addition, endothelial cells synthesize and secrete heparans and growth factors that regulate SMC proliferation.10-13 Finally, endothelial cells can clear and metabolically alter bloodborne and locally produced substances, including plasma lipids and lipoproteins,14 adenine nucleotides and nucleosides,15 serotonin, catecholamines, bradykinin, and angiotensin I.16
Endothelial cells are involved in the metabolism of plasma lipids in several ways. Lipoprotein lipase, an enzyme that hydrolyzes triglycerides into constituent fatty acids, is bound to the endothelial cell surface by heparan sulfates.17 The interaction of this enzyme with chylomicrons or very low-density lipoprotein particles results in the release of free fatty acids, which can then cross the subendothelial space to the underlying SMC or inflammatory cells in atherosclerosis. In addition, endothelial cells possess receptors for low-density lipoprotein (LDL),18 which regulate the transport and modification of ...