2. Academic Validation
  3. Endothelial SCUBE2 Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis

Endothelial SCUBE2 Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis

  • Arterioscler Thromb Vasc Biol. 2017 Jan;37(1):144-155. doi: 10.1161/ATVBAHA.116.308546.
Yuh-Charn Lin 1,  Tsu-Yi Chao 1,  Chi-Tai Yeh 1,  Steve R Roffler 1,  Reiji Kannagi 1,  Ruey-Bing Yang 2
Affiliations

Affiliations

  • 1 From the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (Y.-C.L., S.R.R., R.K., R.-B.Y.); Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taiwan (T.-Y.C., C.-T.Y.); Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (T.-Y.C.); Department of Medical Research and Education, Shuang Ho Hospital, Taipei Medical University, Taiwan (C.-T.Y.); and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan (R.-B.Y.).
  • 2 From the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (Y.-C.L., S.R.R., R.K., R.-B.Y.); Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taiwan (T.-Y.C., C.-T.Y.); Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (T.-Y.C.); Department of Medical Research and Education, Shuang Ho Hospital, Taipei Medical University, Taiwan (C.-T.Y.); and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan (R.-B.Y.). rbyang@ibms.sinica.edu.tw.
PMID: 27834687 DOI: 10.1161/ATVBAHA.116.308546
Abstract

Objective: Vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, exerts its proangiogenic action by binding to VEGFR2 (VEGF receptor 2), the activity of which is further modulated by VEGFR2 coreceptors such as neuropilins. However, whether VEGFR2 is regulated by additional coreceptors is not clear. To investigate whether SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2), a peripheral membrane protein expressed in vascular endothelial cells (ECs) known to bind Other signaling receptors, functions as a VEGFR2 coreceptor and to verify the role of SCUBE2 in the VEGF-induced angiogenesis.

Approach and results: SCUBE2 lentiviral overexpression in human ECs increased and short hairpin RNA knockdown inhibited VEGF-induced EC growth and capillary-like network formation on Matrigel. Like VEGF, endothelial SCUBE2 was upregulated by hypoxia-inducible factor-1α at both mRNA and protein levels. EC-specific Scube2 knockout mice were not defective in vascular development but showed impaired VEGF-induced neovascularization in implanted Matrigel plugs and recovery of blood flow after hind-limb ischemia. Coimmunoprecipitation and ligand-binding assays showed that SCUBE2 forms a complex with VEGF and VEGFR2, thus acting as a coreceptor to facilitate VEGF binding and augment VEGFR2 signal activity. SCUBE2 knockdown or genetic knockout suppressed and its overexpression promoted the VEGF-induced activation of downstream proangiogenic and proliferating signals, including VEGFR2 phosphorylation and mitogen-activated protein kinase or Akt activation.

Conclusions: Endothelial SCUBE2 may be a novel coreceptor for VEGFR2 and potentiate VEGF-induced signaling in adult angiogenesis.

Keywords

HIF1A protein, human; SCUBE2 protein, human; angiogenesis modulators; endothelial cells; vascular endothelial growth factor A.

Figures