FIGURE F13.1.1 • Schematic diagram of cellular interactions in the formation of an atheromatous plaque. Endothelial cells express cell adhesion molecules that initiate monocyte migration through the endothelium. Platelet-derived growth factor (PDGF) and other growth factors (blue arrow) released from endothelial cells stimulate migration of the smooth muscle cells from the tunica media to the tunica intima. In the tunica intima, smooth muscle cells produce large amounts of extracellular matrix (proteoglycans, collagen) that increase the thickness of the tunica intima. Foam cells derived from both macrophages and smooth muscle cells accumulate LDLs, which cross the endothelial barrier (yellow arrows) and are oxidized by free radicals produced by the endothelial cells. lumen lipid uptake cell adhesion molecules endothelium tunicaintimainternal elastic membrane tunicamediamonocyte smooth muscle cells cytokines oxidized LDL foam cells LDL LDL PDGF continued next page free radicals produced by endothelial cells. Modified LDLs, in turn, are rapidly endocytosed by macrophages to form foam cells (see Fig. F13.1.1). Foam cells are a characteristic feature in the formation of atheromatous plaques.
Endothelium of blood vessels controls contraction and relaxation of smooth muscle cells in the tunica media influencing local blood flow and pressure.
The endothelial-derived relaxing factor (EDRF) was historically one of the early compounds discovered in the endothelial cells that was causing relaxation of blood vessels. For years, researchers had difficulty characterizing EDRF chemically. It is now known that most of the vascular effects of EDRF can be attributed to nitric oxide (NO) and its related compounds, which are released by endothelial cells in arteries, blood capillaries, and even lymphatic capillaries. As a chemical compound, NO is a gas with a very short physiologic half-life measured in seconds; hence, the difficulty with its discovery.
Shear stress produced during the interaction of blood flow with vascular endothelial cells initiates nitric oxide (NO)-derived relaxation of blood vessels.
Vasodilation (the relaxation of smooth muscle cells) increases the luminal diameter of the vessels, decreasing vascular resistance and systemic blood pressure. Endotheliumderived nitric oxide (NO) is one of several critical regulators of cardiovascular homeostasis. It regulates the blood vessel diameter, inhibits monocyte adhesion to dysfunctional endothelial cells, and maintains an antiproliferative and anti-apoptotic environment in the vessel wall. NO is an endogenous vasodilatory gas continuously synthesized in endothelial cells by endothelial nitric oxide synthase (eNOS). This Ca2-dependent enzyme catalyzes oxidation of L-arginine and acts through the G-protein–signaling cascade. Endothelial cells are constantly subjected to shear stress, the dragging force generated by the blood flow. Shear stress increases synthesis of a potent eNOS stimulator, the vascular endothelial growth factor (VEGF), and triggers a variety of other molecular and physical changes in endothelial cell structure and function. Once NO is produced by endothelial cells, it diffuses out through the cell and basement membrane to the underlying tunica media and binds to guanylate cyclase in smooth muscle cytoplasm. This enzyme increases production of cGMP, which activates smooth muscle protein kinase G (PKG). Activation of protein kinase G has a negative effect on intracellular concentration of Ca2, causing smooth muscle relaxation (Fig 13.12). Note that NO is also a signaling molecule in many pathologic and physiologic processes.