Plasticity of Arterial and Venous Endothelial Cell Identity: Some Nerve!

The vascular endothelium, the innermost lining of the blood vessel wall, forms a critical barrier between blood and all tissues. Endothelial injury in large caliber arteries contributes to coronary artery disease, stroke, and peripheral artery disease, whereas endothelial injury in veins may predispose to venous thromboembolic disease such as deep vein thrombosis and pulmonary embolism. Accumulating studies over the past few decades revealed that endothelial cells (ECs) from arteries, veins, and lymphatic vessels exhibit important differences with respect to their appearance, function, regenerative capacity, and molecular repertoire. The identification of specific markers for arterial (EphrinB2) and venous (EphB4) ECs lead to the appreciation that upstream signaling pathways may govern arterial versus venous EC fate specification.1–4 For example, vascular endothelial growth factor (VEGF)-mediated induction of extracellular signal regulated kinase (ERK) activation facilitates the induction of Dll4/Notch signaling leading to arterial EphrinB2 expression.2–4 In contrast, transcriptional activation of Coup-TFII (chicken ovalbumin upstream promoter transcription factor II) inhibits the VEGF receptor neuropilin to suppress notch signaling, thereby inducing venous marker expression.5 The role of VEGF in promoting arterial EC identity has been well recognized from genetic ablation studies across species. However, VEGF-independent mechanisms may also be contributory as suggested by the observation that arterial VEGF expression is significantly reduced after birth.6 In addition, the heterogeneity of ECs within the vessel wall7 raises the question of flexibility of EC identity toward arterial or venous differentiation. In keeping with this, arterial cells contribute to venous vessels, and venous cells may differentiate into arteries or lymphatic ECs in zebrafish embryos.8,9 Collectively, these studies suggest that extrinsic factors, potentially independent of VEGF, may govern EC fate plasticity during development and in their maintenance in adult vessels. Article, see p 607 In this issue of Circulation …

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