FGFR1 SUMOylation coordinates endothelial angiogenic signaling in angiogenesis

Abstract

Angiogenesis contributes fundamentally to embryonic development, tissue homeostasis, and wound healing. Basic fibroblast growth factor (FGF2) is recognized as the first proangiogenic molecule discovered, and it facilitates angiogenesis by activating FGF receptor 1 (FGFR1) signaling in endothelial cells. However, the precise roles of FGFR and the FGF/FGFR signaling axis in angiogenesis remain unclear, especially because of the contradictory phenotypes of in vivo FGF and FGFR gene deficiency models. Our previous study results suggested a potential role of posttranslational small ubiquitin-like modifier modification (SUMOylation), with highly dynamic regulatory features, in vascular development and disorder. Here, we identified SENP1-regulated endothelial FGFR1 SUMOylation at conserved lysines responding to proangiogenic stimuli, while SENP1 functioned as the deSUMOylase. Hypoxia-enhanced FGFR1 SUMOylation restricted the tyrosine kinase activation of FGFR1 by modulating the dimerization of FGFR1 and FGFR1 binding with its phosphatase PTPRG. Consequently, it facilitated the recruitment of FRS2α to VEGFR2 but limited additional recruitment of FRS2α to FGFR1, supporting the activation of VEGFA/VEGFR2 signaling in endothelial cells. Furthermore, SUMOylation-defective mutation of FGFR1 resulted in exaggerated FGF2/FGFR1 signaling but suppressed VEGFA/VEGFR2 signaling and the angiogenic capabilities of endothelial cells, which were rescued by FRS2α overexpression. Reduced angiogenesis and endothelial sprouting in mice bearing an endothelial-specific, FGFR1 SUMOylation-defective mutant confirmed the functional significance of endothelial FGFR1 SUMOylation in vivo. Our findings identify the reversible SUMOylation of FGFR1 as an intrinsic fine-tuned mechanism in coordinating endothelial angiogenic signaling during neovascularization; SENP1-regulated FGFR1 SUMOylation and deSUMOylation controls the competitive recruitment of FRS2α by FGFR1 and VEGFR2 to switch receptor-complex formation responding to hypoxia and normoxia angiogenic environments.

Endothelial FIS1 DeSUMOylation Protects Against Hypoxic Pulmonary Hypertension

“…37 Our previously obtained data showed the role of SENP1mediated deSUMOylation in ischemia and vascular defects, 38 and our studies also revealed the pivotal role of SUMOylation in endothelial activation in graft arteriosclerosis and endothelial growth in angiogenesis. [39][40][41] In the present study, we uncovered an intrinsic SUMOylationmediated regulation of mitochondrial homeostasis in pulmonary ECs to preserve pulmonary endothelial function in response to hypoxic stress during PH.…”

SENP2 Promotes VSMC Phenotypic Switching via Myocardin De-SUMOylation

“…Six isoforms of SENPs have been identified in humans (SENP1, SENP2, SENP3, SENP5, SENP6, and SENP7) [ 16 ]. While previous studies have mainly focused on the pivotal role of SENPs in the development of cancer [ 17 , 18 , 19 , 20 , 21 , 22 ], in recent years, the role of SENPs and SUMOylation in vascular diseases has attracted considerable attention [ 14 , 23 , 24 , 25 , 26 , 27 ]. SENP1 modulates the SUMOylation of GATA2 and leads to endothelial dysfunction in graft atherosclerosis [ 23 ].…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“… 997 The dynamic SUMOylation of endothelial FGFR1 regulates the balance of the angiogenesis core pathways VEGF/VEGFR and FGF/FGFR and enables the body to complete angiogenesis in different microenvironments. 1003 SUMOylation also plays an important role in the generation of germ cells. SUMO1 and SUMO2/3 function at different stages of male meiosis and precisely regulate the formation of sex chromosomes.…”

“…Endothelial SENP1 deletion in newly generated mice significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling 997 . The dynamic SUMOylation of endothelial FGFR1 regulates the balance of the angiogenesis core pathways VEGF/VEGFR and FGF/FGFR and enables the body to complete angiogenesis in different microenvironments 1003 . SUMOylation also plays an important role in the generation of germ cells.…”