2. Academic Validation
  3. BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF

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

  • Angiogenesis. 2021 Feb;24(1):129-144. doi: 10.1007/s10456-020-09748-4.
H H Pulkkinen # 1,  M Kiema # 1,  J P Lappalainen 1 2,  A Toropainen 1,  M Beter 1,  A Tirronen 1,  L Holappa 1,  H Niskanen 1,  M U Kaikkonen 1,  S Ylä-Herttuala # 1 3 4,  Johanna P Laakkonen # 5
Affiliations

Affiliations

  • 1 A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • 2 Department of Clinical Chemistry, University of Eastern Finland and Eastern Finland Laboratory Centre, Kuopio, Finland.
  • 3 Science Service Center, Kuopio University Hospital, Kuopio, Finland.
  • 4 Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.
  • 5 A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. johanna.p.laakkonen@uef.fi.
  • # Contributed equally.
PMID: 33021694 DOI: 10.1007/s10456-020-09748-4
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/KDR/Flk-1) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2/KDR/Flk-1 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/KDR/Flk-1 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.

Keywords

Angiogenesis; BMP2; BMP6; Bone morphogenetic protein; Hippo signaling pathway; VEGF; VEGFR2; Vascular endothelial growth factor.

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