title: Rnd3/RhoE Modulates Hypoxia-Inducible Factor 1α/Vascular Endothelial Growth Factor Signaling by Stabilizing Hypoxia-Inducible Factor 1α and Regulates Responsive Cardiac Angiogenesis.
abstract: The insufficiency of compensatory angiogenesis in the heart of patients with hypertension contributes to heart failure transition. The hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the proangiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a proangiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this proangiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3(+/-)) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The poststress Rnd3(+/-) hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardioprotective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel proangiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in patients with heart failure may explain the insufficient compensatory angiogenesis involved in the transition to heart failure.
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yue
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Tingli
authors.initials: T
authors.lastname: Yang
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Tianfa
authors.initials: T
authors.lastname: Li
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Junli
authors.initials: J
authors.lastname: Guo
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Jianjian
authors.initials: J
authors.lastname: Shi
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Guillermo
authors.initials: G
authors.lastname: Torre-Amione
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.).
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: Andrade
authors.affiliation: From the Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (X.Y., Y.Y.); Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston (X.Y., X.L., T.Y., X.Y., Y.D., K.C.A., J.C.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (X.Y., X.J., X.L.); Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China (T.L., J.G.); Department of Pediatrics, Indiana University School of Medicine, Indianapolis (J.S., L.W.); and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX (K.A.Y., G.T.-A.). jchang@ibt.tamhsc.edu.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; C513341:Rnd3 protein, mouse; D020741:rho GTP-Binding Proteins
keywords: G-protein; angiogenesis factor; heart failure; hypertension; hypertrophy; vascular endothelial growth factor A