BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF

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.

A positive feedback loop between TAZ and miR-942-3p modulates proliferation, angiogenesis, epithelial-mesenchymal transition process, glycometabolism and ROS homeostasis in human bladder cancer

“…The Hippo pathway has emerged as an important upstream signaling pathway in angiogenesis [53]. In detail, TAZ has been reported to be involved in VEGF-induced endothelial cell sprouting [54]. In addition, TAZ also enhances angiogenesis in EGFR wild-type non-small cell lung cancer cells [55].…”

The Role of BMP Signaling in Endothelial Heterogeneity

“…Moreover, Notch renders the responsiveness of ECs toward pro-angiogenic BMP stimuli, BMP2 and BMP6, by regulating the expression of SMAD6, which ultimately contributes to the phosphorylation of SMAD1/5 and a tip cell phenotype (Mouillesseaux et al, 2016). Recent findings also implicated synergistic effects of BMP signaling and VEGF signaling on tip cell-associated markers VEGFR2 and DLL4 (Pulkkinen et al, 2020). Furthermore, Notch signaling also appears to influence BMP signaling at the effector level since the expression of Herp2 in ECs is co-modulated by Notch and BMP6 signaling (Itoh et al, 2004).…”

“…In addition to mechanical forces, recent studies reported hypoxia as one of the potential modulators for BMP signaling. Under hypoxic conditions, differential expression of BMP ligands could be observed in comparison to normoxic conditions ( Pulkkinen et al, 2021 ). Moreover, BMP signaling could also attenuate hypoxic responses in ECs through the ALK1/SMAD/ATOH8 axis, ultimately impeding the development of pulmonary arterial hypertension (PAH) ( Morikawa et al, 2019 ).…”

The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology

“…In the circulatory system, numerous cooperation between VEGF signaling and BMP signaling have been reported (Figure 2; number 7). For instance, BMP2/6/9, but also Bmper and Endoglin, are all induced by VEGF in the endothelium, in vitro and in vivo [180]. Conversely, the development of the outflow tract in the mouse heart is controlled by BMP4/7-SMAD-mediated direct and indirect repression of Vegf-a [181].…”

“…Indeed, the pro-angiogenic activity of BMP4 in HUVECs is mediated by a BMPRII-mediated intracellular transactivation of VEGFR2 via c-Src [183]. Recently, Pulkkinen et al showed through in vitro and in vivo studies that BMP2, but also BMP6, signaling causes VEGFR2-mediated vessel sprouting [180].…”