| Title | KANK4 Promotes Arteriogenesis by Potentiating VEGFR2 Signaling in a TALIN-1-Dependent Manner |
| Authors | Zhang, Chonghe He, Hao Dai, Jianing Li, Yunxia He, Jing Yang, Wu Dai, Jialin Han, Feng Kong, Wenyan Wang, Xiaohong Zheng, Xiangjian Zhou, Jing Pan, Weijun Chen, Zhongwen Mahak, Singhal Zhang, Yaoyang Guo, Feng Hu, Junhao |
| Affiliation | Chinese Acad Sci, Interdisciplinary Res Ctr Biol & Chem, Shanghai Inst Organ Chem, 100 Haike Rd, Shanghai 203201, Peoples R China Univ Chinese Acad Sci, Beijing, Peoples R China Tianjin Med Univ, Sch Basic Med Sci, Dept Pharmacol, Tianjin, Peoples R China Tianjin Med Univ, Sch Basic Med Sci, Tianjin Key Lab Inflammat Biol, Tianjin, Peoples R China Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Key Lab Mol Cardiovasc Sci,Minist Educ, Beijing, Peoples R China Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Shanghai, Peoples R China German Canc Res Ctr DKFZ ZMBH Alliance, Div Vasc Oncol & Metastasis, Heidelberg, Germany Heidelberg Univ, Med Fac Mannheim, European Ctr Angiosci ECAS, Dept Vasc Biol & Tumor Angiogenesis, Heidelberg, Germany Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Plast Surg, 600 Yishan Rd, Shanghai 200233, Peoples R China |
| Keywords | LUMEN FORMATION LIMB ISCHEMIA BYPASS ANGIOGENESIS INTEGRINS PROTEINS ARTERIAL FAMILY GROWTH DOMAIN |
| Issue Date | Jun-2022 |
| Publisher | ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY |
| Abstract | Background: Arteriogenesis plays a critical role in maintaining adequate tissue blood supply and is related to a favorable prognosis in arterial occlusive diseases. Strategies aimed at promoting arteriogenesis have thus far not been successful because the factors involved in arteriogenesis remain incompletely understood. Previous studies suggest that evolutionarily conserved KANK4 (KN motif and ankyrin repeat domain-containing proteins 4) might involve in vertebrate vessel development. However, how the KANK4 regulates vessel function remains unknown. We aim to determine the role of endothelial cell-specifically expressed KANK4 in arteriogenesis. Methods: The role of KANK4 in regulating arteriogenesis was evaluated using Kank4(-/-) and KANK4(iECOE) mice. Molecular mechanisms underlying KANK4-potentiated arteriogenesis were investigated by employing RNA transcriptomic profiling and mass spectrometry analysis. Results: By analyzing Kank4-EGFP reporter mice, we showed that KANK4 was specifically expressed in endothelial cells. In particular, KANK4 displayed a dynamic expression pattern from being ubiquitously expressed in all endothelial cells of the developing vasculature to being explicitly expressed in the endothelial cells of arterioles and arteries in matured vessels. In vitro microfluidic chip-based vascular morphology analysis and in vivo hindlimb ischemia assays using Kank4(-/-) and KANK4(iECOE) mice demonstrated that deletion of KANK4 impaired collateral artery growth and the recovery of blood perfusion, whereas KANK4 overexpression leads to increased vessel caliber and blood perfusion. Bulk RNA sequencing and Co-immunoprecipitation/mass spectrometry (Co-IP/MS) analysis identified that KANK4 promoted EC proliferation and collateral artery remodeling through coupling VEGFR2 (vascular endothelial growth factor receptor 2) to TALIN-1, which augmented the activation of the VEGFR2 signaling cascade. Conclusions: This study reveals a novel role for KANK4 in arteriogenesis in response to ischemia. KANK4 links VEGFR2 to TALIN-1, resulting in enhanced VEGFR2 activation and increased EC proliferation, highlighting that KANK4 is a potential therapeutic target for promoting arteriogenesis for arterial occlusive diseases. |
| URI | http://hdl.handle.net/20.500.11897/646692 |
| ISSN | 1079-5642 |
| DOI | 10.1161/ATVBAHA.122.317711 |
| Indexed | SCI(E) |
| Appears in Collections: | 基础医学院 |
