In most regions, the interendothelial junctions normally are impermeable. However, these junctions open under the influence of hemodynamic stress (e.g., high blood pressure) and/or vasoactive agents (e.g., histamine in inflammation), flooding the adjacent tissues with electrolytes and protein. Vacuolar transcytosis also permits the movement of large amounts of solutes across intact endothelium. Relevant to pathologic processes, ECs also are active participants in the egress of leukocytes during inflammatory cell recruitment (Chapter 3), and EC dysfunction underlies development of atherosclerosis (discussed later).
Although ECs throughout the vasculature share many attributes, they also show phenotypic variability and adaptations depending on the anatomic site and local environmental cues. Thus, EC populations from different parts of the vasculature (e.g., large vessels versus capillaries, or arteries versus veins) have distinct transcriptional programs and behaviors. Fenestrations (holes) in ECs lining hepatocyte cords, renal glomeruli, and choroid plexus are specializations that facilitate filtration. Conversely, in the central nervous system, ECs—in conjunction with astrocytes— collaborate to generate an impermeable blood-brain barrier.
Maintenance of a “normal,” nonthrombogenic EC lining requires laminar flow, certain growth factors (e.g., vascular endothelial growth factor [VEGF]), and firm adhesion to the underlying basement membrane (
Fig. 10.2 ). Trauma or other injuries that denude vessel walls of ECs tip the scales toward thrombosis and vasoconstriction. However, ECs also respond to various physiologic and pathologic stimuli by modulating their usual (constitutive) functions and by expressing new (inducible) properties—a process called endothelial activation.
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Inducers of endothelial activation include bacterial products, inflammatory cytokines, hemodynamic stresses and lipid products (relevant to atherosclerosis, discussed later), advanced glycation end products (important in diabetic vascular injury), viruses, complement, and various metabolic insults (e.g., hypoxia) (see
Fig. 10.2 ). Activated ECs undergo shape changes, express adhesion molecules, and produce cytokines, chemokines, growth factors, pro-coagulant and anti-coagulant factors, and a host of other biologically active products—all presumably intended to respond to the original stimulus.
Some of these responses are rapid (occurring within minutes), reversible, and independent of new protein synthesis (e.g., endothelial contraction induced by histamine); others involve alterations in gene and protein expression, and may take days to develop or abate. Exposure of ECs to high levels of stimuli for sustained periods can result in endothelial dysfunction, characterized by impaired endothelium-dependent vasodilation, hypercoagulable states, and increased oxygen free radical production. Dysfunctional endothelium can initiate thrombosis, promote atherosclerosis, or contribute to formation of the vascular lesions of hypertension and diabetes.
SMCs participate in both normal vascular repair and pathologic processes such as atherosclerosis. When stimulated by various factors, SMCs can do the following:
Upregulate ECM collagen, elastin, and proteoglycan production
SMCs also mediate the vasoconstriction or vasodilation that occurs in response to physiologic or pharmacologic stimuli.