Qiulun Lu1, Zhonglin Xie1, Chenghui Yan1, Ye Ding1, Zejun Ma1, Shengnan Wu1, Yu Qiu1, Stephanie M Cossette1, Michelle Bordas1, Ramani Ramchandran2, Ming-Hui Zou2. 1. From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Q.L., Z.X., C.Y., Y.D., Z.M., S.W., Y.Q., M.-H.Z.); and Division of Neonatology, Department of Pediatrics (S.M.C., M.B., R.R.) and Obstetrics and Gynecology (OBGYN), Developmental Vascular Biology Program, Children's Research Institute (R.R.), Medical College of Wisconsin, Milwaukee. 2. From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta (Q.L., Z.X., C.Y., Y.D., Z.M., S.W., Y.Q., M.-H.Z.); and Division of Neonatology, Department of Pediatrics (S.M.C., M.B., R.R.) and Obstetrics and Gynecology (OBGYN), Developmental Vascular Biology Program, Children's Research Institute (R.R.), Medical College of Wisconsin, Milwaukee. mzou@gsu.edu rramchan@mcw.edu.
Abstract
OBJECTIVE: SNRK (sucrose nonfermenting 1-related kinase) is a novel member of the AMPK (adenosine monophosphate-activated protein kinase)-related superfamily that is activated in the process of angiogenesis. Currently, little is known about the function of SNRK in angiogenesis in the physiological and pathological conditions. APPROACH AND RESULTS: In this study, in Snrk global heterozygous knockout mice, retina angiogenesis and neovessel formation after hindlimb ischemia were suppressed. Consistently, mice with endothelial cell (EC)-specific Snrk deletion exhibited impaired retina angiogenesis, and delayed perfusion recovery and exacerbated muscle apoptosis in ischemic hindlimbs, compared with those of littermate wide-type mice. Endothelial SNRK expression was increased in the extremity vessel samples from nonischemic human. In ECs cultured in hypoxic conditions, HIF1α (hypoxia inducible factor 1α) bound to the SNRK promoter to upregulate SNRK expression. In the nuclei of hypoxic ECs, SNRK complexed with SP1 (specificity protein 1), and together, they bound to an SP1-binding motif in the ITGB1 (β1 integrin) promoter, resulting in enhanced ITGB1 expression and promoted EC migration. Furthermore, SNRK or SP1 deficiency in ECs ameliorated hypoxia-induced ITGB1 expression and, consequently, inhibited EC migration and angiogenesis. CONCLUSIONS: Taken together, our data have revealed that SNRK/SP1-ITGB1 signaling axis promotes angiogenesis in vivo.
OBJECTIVE:SNRK (sucrose nonfermenting 1-related kinase) is a novel member of the AMPK (adenosine monophosphate-activated protein kinase)-related superfamily that is activated in the process of angiogenesis. Currently, little is known about the function of SNRK in angiogenesis in the physiological and pathological conditions. APPROACH AND RESULTS: In this study, in Snrk global heterozygous knockout mice, retina angiogenesis and neovessel formation after hindlimb ischemia were suppressed. Consistently, mice with endothelial cell (EC)-specific Snrk deletion exhibited impaired retina angiogenesis, and delayed perfusion recovery and exacerbated muscle apoptosis in ischemic hindlimbs, compared with those of littermate wide-type mice. Endothelial SNRK expression was increased in the extremity vessel samples from nonischemic human. In ECs cultured in hypoxic conditions, HIF1α (hypoxia inducible factor 1α) bound to the SNRK promoter to upregulate SNRK expression. In the nuclei of hypoxic ECs, SNRK complexed with SP1 (specificity protein 1), and together, they bound to an SP1-binding motif in the ITGB1 (β1 integrin) promoter, resulting in enhanced ITGB1 expression and promoted EC migration. Furthermore, SNRK or SP1 deficiency in ECs ameliorated hypoxia-induced ITGB1 expression and, consequently, inhibited EC migration and angiogenesis. CONCLUSIONS: Taken together, our data have revealed that SNRK/SP1-ITGB1 signaling axis promotes angiogenesis in vivo.
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