BMPER Is an Endothelial Cell Regulator and Controls Bone Morphogenetic Protein-4–Dependent Angiogenesis

Abstract

Abstract-Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. BMPER (BMP endothelial cell precursor-derived regulator) is a differentially expressed protein in embryonic endothelial precursor cells. In earlier work, we found that BMPER interacts with BMPs and when overexpressed antagonizes their function in embryonic axis formation. In contrast, in a BMPER-deficient zebrafish model, BMPER behaves as a BMP agonist. Furthermore, lack of BMPER induces a vascular phenotype in zebrafish that is driven by disarray of the intersomitic vasculature. Here, we investigate the impact of BMPER on endothelial cell function and signaling and elucidate its role in BMP-4 function in gain-and loss-of-function models. As shown by Western blotting and immunocytochemistry, BMPER is an extracellular matrix protein expressed by endothelial cells in skin, heart, and lung. We show that BMPER is a downstream target of FoxO3a and consistently exerts activating effects on endothelial cell sprouting and migration in vitro and in vivo. Accordingly, when BMPER is depleted from endothelial cells, sprouting is impaired. In terms of BMPER related intracellular signaling, we show that BMPER is permissive and necessary for Smad 1/5 phosphorylation and induces Erk1/2 activation. Most interestingly, BMPER is necessary for BMP-4 to exert its activating role in endothelial function and to induce Smad 1/5 activation. Vice versa, BMP-4 is necessary for BMPER activity. Taken together, BMPER is a dose-dependent endothelial cell activator that plays a unique and pivotal role in fine-tuning BMP activity in angiogenesis. Key Words: BMPER Ⅲ bone morphogenetic proteins Ⅲ vascular biology Ⅲ endothelial cell function Ⅲ signaling A ngiogenesis is a basic biological event that is involved in embryonic development but also in adult physiological and pathological conditions, such as inflammation, tumor growth, atherosclerosis, or response to ischemia. This process depends on the orchestrated function of intra-and extracellular proteins, many of which are conserved from embryonic development through adulthood. 1 Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-␤ superfamily. Originally, they have been identified by their ability to induce ectopic bone formation and have been extensively studied during embryonic development, in which they control axis formation and organogenesis. Today, more than 20 BMP-related proteins and a number of BMP modulating proteins have been identified. 2 A growing body of evidence suggests that they serve as important regulators in vascular development and disease. 3 BMPs are extracellular proteins that signal through cell surface complexes of type I and type II serine/threonine kinase receptors. On activation, the receptors mediate intracellular signaling mainly through the Smad 1/5 transcription factors. BMP signaling is regulated at several levels: activity of R-Smads (1/5) is modulated by facilitating (eg, Smad 4) or inhibitory (eg,...

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