Abstract
The BMP/TGFβ-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.
Highlights
Aberrant vascular endothelial growth factor 2 (VEGFR2) signaling and increased VEGF expression has been connected to pathological angiogenesis in various vascular diseases and cancer [1,2,3,4]
Our findings demonstrate that (i) several bone morphogenetic proteins (BMPs) are regulated after systemic VEGF-induced angiogenesis and in normoxic endothelial cells, (ii) BMPs are regulated after acute myocardial ischemia, and in hypoxic endothelial cells, (iii) BMP2 and BMP6 synergistically modulate VEGF-induced endothelial cell sprouting via regulating VEGFR, Notch or TAZ-Hippo signaling, and (iv) BMP6 protein is pro-angiogenic in vivo
Confluent cultures of Human umbilical vein endothelial cells (HUVECs) were washed with PBS, followed by starvation of cells for 16 h with EGM medium supplemented with 0.5% FBS
Summary
Aberrant vascular endothelial growth factor 2 (VEGFR2) signaling and increased VEGF expression has been connected to pathological angiogenesis in various vascular diseases and cancer [1,2,3,4]. VEGF-mediated gene transfer has been used to induce vascular growth in myocardium and skeletal muscle to treat ischemia [5, 6]. Nextgeneration sequencing analyses of VEGF-induced effects in endothelial cells have been performed [7,8,9], the crosstalk of multiple cell types, and other growth factor pathways regulating VEGF-induced angiogenesis are still poorly understood. Dysfunctional BMP signaling is involved in various vascular disorders, such as hereditary hemorrhagic telangiectasia, cerebral cavernous malformation, pulmonary arterial hypertension and atherosclerosis [10,11,12].
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