Deep-vein thrombosis, varicose veins, and post-thrombotic syndrome all are associated with abnormalities of the bicuspid venular valves. From the time of Virchow, clinicians have recognized that stagnation of blood flow at the valve leaflet/vessel wall junction initiates microthrombus formation. Recent studies have demonstrated that aging, a significant risk factor for venous thrombosis, is associated with thickening of the venous valve leaflets, which in turn is inversely related to valve function.1 Furthermore, valvular sinus endothelium maintains a thrombo-resistant phenotype wherein expression of the anticoagulant proteins thrombomodulin and endothelial protein C receptor is up-regulated and the procoagulant protein von Willebrand factor is down-regulated, compared with vein lumen endothelium.2 Thus, understanding how venous valves operate and mature may aid in developing new therapies for venous hypertension and possibly protect valves, preventing chronic venous insufficiency. Utilizing insights derived from the morphogenesis of cardiac valvular and lymphatic endothelium, Bazigou and colleagues in the laboratory of Taija Makinen at the London Research Institute in the U.K., defined genes responsible for valve development in veins, finding a common molecular mechanism involving integrin-α9 and ephrin-B2 signaling in both veins and lymphatics.
First, the investigators showed that mouse and human venous valves share common morphologic features. Scanning electron micrograph analysis showed that the edges of valve leaflets were lined by transversely aligned fusiform cells, while the cells on the leaflet and downstream on the outflow side of the valve had a rounded morphology. In contrast, endothelial cells located upstream on the inflow side of the valve aligned in the direction of blood flow. Similar cell arrangement was observed around lymphatic valves. In developing mice, venous valves express markers of arterial and lymphatic endothelia, including ephrin-B2, integrin-α9 and its ligand, an alternatively spliced form of fibronectin known as Fn-IIIa. The molecular identity of venous valve endothelial cells was further characterized by examining the expression of prospero-related homeobox 1 (PROX1) and VEGFR3, two major regulators of lymphangiogenesis that are highly expressed in lymphatic valves. Immunofluorescence staining revealed strong and specific expression of PROX1 in the endothelial cells of developing and mature murine venous valves. PROX1 was also expressed in human venous valves. Valveselective deletion of integrin-α9 and ephrin-B2 disrupted venous valve morphogenesis, demonstrating the continuous requirement of integrin-α9 and ephrin-B2 signaling for the maintenance of venous valves. Ephrin-B2, but not integrin-α9, was additionally required for the maintenance of lymphatic valves.
In Brief
These studies describe the molecular regulators of venous valves and the remarkable involvement of common morphogenetic processes and signaling pathways in controlling valve formation in veins and lymphatic vessels. Potentially, agents that modulate integrin-α9 and ephrin-B2 may prevent venous hypertension and even the post-thrombotic syndrome. Could the thickening of the valve leaflets be due to excess connective tissue matrix proteins expressed in response to stimuli such as thrombin or cytokines? Nature’s parsimony is always fascinating. Might lymphatic dysfunction go hand-in-hand with venous valve dysfunction? Might the bad edema cases be a double-whammy for activating a few key mediators locally? Or might this explain the occasional patient who gets lymphedema even after superficial phlebitis?
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Competing Interests
Dr. Vercellotti indicated no relevant conflicts of interest.
