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.). [email protected].
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/KDR/Flk-1 (VEGF receptor 2), the activity of which is further modulated by VEGFR2/KDR/Flk-1 coreceptors such as neuropilins. However, whether VEGFR2/KDR/Flk-1 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/KDR/Flk-1 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/KDR/Flk-1, thus acting as a coreceptor to facilitate VEGF binding and augment VEGFR2/KDR/Flk-1 signal activity. SCUBE2 knockdown or genetic knockout suppressed and its overexpression promoted the VEGF-induced activation of downstream proangiogenic and proliferating signals, including VEGFR2/KDR/Flk-1 phosphorylation and mitogen-activated protein kinase or Akt activation.

Conclusions: Endothelial SCUBE2 may be a novel coreceptor for VEGFR2/KDR/Flk-1 and potentiate VEGF-induced signaling in adult angiogenesis.

Keywords

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

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