FIGURE 1.

EC segmental differences and the homeostatic regulation of blood flow, hemostasis, permeability, and inflammation. ECs lining the arterioles are supported by layers of SMCs, whereas those in the capillary and venular segments are supported by a single, often discontinuous, layer of pericytes. Homeostatic processes are shown in blue, and processes of EC activation are shown in red. A, Blood flow is controlled by differential production of vasodilatory compounds (NO from nitric oxide synthase-3 [NOS3] and prostaglandin [PGI₂] from cyclooxygenase-1 [COX1]) that increase SMC cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), respectively. These agents cause SMCs to relax, increasing the vessel diameter and blood flow. Vasoconstricting ATII is produced from systemically available but inactive angiotensin-1 (AT-1) by angiotensin-converting enzyme (ACE), whereas vasoconstricting ET-1 is produced from EC-secreted big-ET by endothelin converting enzyme (ECE). Both ATII and ET-1 act to increase intracellular calcium (Ca²⁺) in SMCs, causing cell contraction and luminal narrowing to reduce blood flow. B, Platelet adhesion is decreased by EC masking of collagen in the basement membrane and by secretion of proteases ADAMTS-13 and -18 to reduce ultra-large vWF (UL-vWF) to polymers of a more physiologic size and activity. Ectoenzymes (EE) convert platelet-activating adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to adenosine monophosphate (AMP). Platelet activation is also inhibited by EC-secreted PGI₂ and NO. Coagulation is actively inhibited by antithrombin-III (ATIII)-mediated inactivation of Xa and thrombin (Th). In addition, thrombomodulin (TM) binds thrombin and directs it to activate protein C. Tissue factor pathway inhibitor (TFPI) blocks tissue factor (TF) and VIIa. Thrombolysis is activated by EC-secreted tissue plasminogen activator (t-PA) and urokinase (UK). Coagulation may be promoted by downregulating the aforementioned mechanisms as well as increased secretion of UL-vWF, expression of TF, secretion of microparticles that provide lipid and surface that binds TF and activates the coagulation cascade, and secretion of plasminogen activator inhibitor-1 (PAI-1) that blocks thrombolysis by tPA and UK. C, The arteriole and capillary vascular segments may be lined by a continuous layer of ECs, with overlapping borders forming tight junctions characterized by claudin-5, junctional adherens molecules, and occluding-forming transmembrane bands of protein. These proteins directly link to the cytoskeleton and closely apposed to the plasma membranes of adjacent cells, thus preventing paracellular passage of macromolecules (MM). Gases diffuse freely. EC lining of venular segments do not typically form tight junctions and are held together by adherens junctions, characterized by vascular endothelial–cadherin and are much more permeable to passive solute and fluid flow allowing passive reabsorption of water into the vascular space. The flux of fluid is governed by the capillary and interstitial hydrostatic and oncotic pressures (P_c, P_i, π_c, and π_i, respectively) as detailed by Starling’s law, and the endothelium directly controls the reflection coefficient (K_f). Pericyte-derived angiopoietin-1 (ANGPT1) activates TIE2 and stabilizes the EC barrier, whereas its natural antagonist EC-derived angiopoietin-2 (ANGPT2) blocks activation and destabilizes the EC barrier. D, Quiescence of immune cells is mediated by basal secretion of NO. Inflammatory cytokines stimulate ECs to recruit leukocytes by inducing expression of selectins, notably E-selectin (that mediates leukocyte tethering and rolling), secretion and display of chemokines (CK) on the glycocalyx (that activates leukocyte spreading and mobility), and expression of ligands for leukocyte integrins such as ICAM-1 and VCAM-1 all induced by the action of pro-inflammatory cytokines. ANGPT2 antagonizes TIE2 signaling, potentially increasing the effects of pro-inflammatory cytokine signaling. Release of membrane- bound ICAM produces soluble ICAM-1 (sICAM-1), a widely viewed marker of immune activation with undetermined physiologic impact.