Mechanisms of Endothelial Cell Heterogeneity in Health and Disease

Abstract

See related article, pages 200–208 The endothelium is an expansive spatially distributed organ.1 Endothelial cells participate in a large number of physiological processes including the control of vasomotor tone, the trafficking of cells and nutrients, the regulation of permeability, and the maintenance of blood fluidity. In addition, the endothelium mediates new blood vessel formation, contributes to the balance of pro- and antiinflammatory mediators, and may play a role in antigen presentation. In accomplishing these tasks, the endothelium exhibits a remarkable “division of labor”. For example, arteriolar endothelium is primarily responsible for mediating vasomotor tone; endothelium in postcapillary venules regulates leukocyte trafficking; capillary endothelial cells display organ-specific barrier properties (eg, blood brain barrier versus fenestrated, discontinuous endothelium in hepatic sinusoids); and endothelial cells from different vascular beds balance local hemostasis via the expression of site-specific patterns of anticoagulants and procoagulants.2 In recent years, in vivo phage display and direct proteome mapping of the intact vasculature have revealed a rich diversity in endothelial cell surface markers.3,4 Any consideration of the mechanisms underlying endothelial heterogeneity is best framed around the time-honored debate of nature versus nurture (which will be addressed here in reverse order) (Figure). Mechanisms of endothelial cell heterogeneity. Relative importance of epigenetics and microenvironment in mediating site-specific phenotypes is indicated by +. The table is designed to provide a conceptual framework; the scores are largely speculative and will require ongoing experimental validation. ### Nurture Site-specific endothelial cell phenotypes may be initiated and maintained by signals residing in the extracellular environment. The endothelium is analogous to a barcode reader, constantly taking inventory of its surrounding extracellular environment on the luminal side (circulating blood and its constituents), the abluminal side, and at the endothelial junctions. Environmental cues may be classified into biomechanical or biochemical. Biochemical forces include shear stress and strain. …