Regulation of Myoendothelial Junction Formation

See related article, pages 1092–1102 In this issue of Circulation Research , Heberlein et al1 provide exciting new insight into the actions of plasminogen activator (PA) inhibitor (PAI)-1 by illuminating its role in governing the ability of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) to communicate with each other through specialized contacts defined as myoendothelial junctions (MEJs). In the resistance vasculature, MEJs are cellular extensions through the internal elastic lamina (IEL), whereby ECs make physical contact with adjacent VSMCs.2 At points of cell–cell contact, the presence of gap junction channels enables electrical coupling and intercellular diffusion of small solutes (<1 kDa) that govern vasomotor control. Cell–cell signaling through gap junction channels can be regulated acutely (eg, through phosphorylation of key serine residues on connexin subunits), and their protein complexes undergo hourly turnover in the plasma membrane. Such properties imply that the nature of cell–cell signaling through MEJs is under dynamic regulation. Despite implications that the MEJ is itself a dynamic structure, little is known about how MEJ formation and regression are regulated. New findings presented by Heberlein et al1 illustrate how dynamic MEJ formation and signaling may be enhanced or impaired via PAI-1 regulation of the PA system.Plasminogen is synthesized in the liver and released into the circulation as a zymogen of the serine protease, plasmin. The conversion of plasminogen to active plasmin is mediated by tissue (t)-PA and urokinase-type (u)-PA (ie, urokinase). Whereas t-PA is involved primarily in the dissolution of fibrin in the circulation, u-PA binds to the urokinase receptor (uPAR) (ie, CD87) on cell membranes, thereby localizing proteolytic activity to the vicinity of binding. In this manner, uPAR is integral to cell migration and adhesion through breakdown of the extracellular matrix (ECM).3,4 PAI-1, a ≈45-kDa glycoprotein, is a serine …