Open AccessRIPK3 modulates growth factor receptor expression in endothelial cells to support angiogenesis
Author(s) -
Siqi Gao,
Courtney T. Griffin
Publication year - 2021
Publication title -
angiogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.061
H-Index - 88
eISSN - 1573-7209
pISSN - 0969-6970
DOI - 10.1007/s10456-020-09763-5
Subject(s) - angiogenesis , microbiology and biotechnology , vascular endothelial growth factor a , kinase insert domain receptor , vascular endothelial growth factor b , vascular endothelial growth factor , necroptosis , vascular endothelial growth inhibitor , biology , endothelial stem cell , vascular endothelial growth factor c , sprouting angiogenesis , cancer research , programmed cell death , neovascularization , in vitro , biochemistry , apoptosis , vegf receptors
Receptor-interacting protein kinase 3 (RIPK3) is a multifunctional intracellular protein that was first recognized as an important component of the necroptosis programmed cell death pathway. RIPK3 is also highly expressed in non-necroptotic murine embryonic endothelial cells (ECs) during vascular development, indicating its potential contribution to angiogenesis. To test this hypothesis, we generated mice lacking endothelial RIPK3 and found non-lethal embryonic and perinatal angiogenesis defects in multiple vascular beds. Our in vitro data indicate that RIPK3 supports angiogenesis by regulating growth factor receptor degradation in ECs. We found that RIPK3 interacted with the membrane trafficking protein myoferlin to sustain expression of vascular endothelial growth factor receptor 2 (VEGFR2) in cultured ECs following vascular endothelial growth factor A (VEGFA) stimulation. Restoration of myoferlin, which was diminished after RIPK3 knockdown, rescued decreased VEGFR2 expression and vascular sprouting in RIPK3-deficient ECs after VEGFA treatment. In addition, we found that RIPK3 modulated expression of genes involved in endothelial identity by inhibiting ERK signaling independently of growth factor receptor turnover. Altogether, our data reveal unexpected non-necroptotic roles for RIPK3 in ECs and evidence that RIPK3 promotes developmental angiogenesis in vivo.