CELSR1 Is a Positive Regulator of Endothelial Cell Migration and Angiogenesis

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Yi-Hong Zhan^1,2#, Qi-Cong Luo^3#, Xiao-Rong Zhang², Nai-An Xiao¹, Cong-Xia Lu¹, Cen Yue¹, Ning Wang^4*, and Qi-Lin Ma^1*

¹The First Affiliated Hospital of Xiamen University, Department of Neurology, 361003 Xiamen, China; E-mail: qilinma@yeah.net

²Fujian Medical University, Center of Neuroscience, The First Affiliated Hospital, The First Clinical Medical College, 350005 Fuzhou, China

³The First Affiliated Hospital of Xiamen University, Center for Laboratory, 361003 Xiamen, China

⁴Fujian Medical University, Center of Neuroscience, The First Affiliated Hospital, Department of Neurology and Institute of Neurology, 350005 Fuzhou, China; E-mail: ningwang@mail.fjmu.edu.cn

^# These authors contributed equally to this work.

^* To whom correspondence should be addressed.

Received January 28, 2016

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Cadherin is an epidermal growth factor and laminin-G seven-pass G-type receptor 1 (CELSR1) is a key component of the noncanonical Wnt/planar cell polarity (PCP) pathway that critically regulates endothelial cell proliferation and angiogenesis. In this study, we examined the biological significance of CELSR1 in endothelial cell migration and angiogenesis. For this, we applied both gain-of-function and loss-of-function approaches. To increase the endogenous expression of CELSR1, we used the transcription activator-like effector (TALE) technology and constructed an artificial TALE-VP64 activator. To knock down the expression of CELSR1, we generated lentivirus containing short hairpin RNA sequences targeting different regions of CELSR1 mRNA. Following up- or down-regulation of CELSR1 in human aortic endothelial cells (HAEC), we assessed in vitro cell proliferation by MTT assay, migration by scratch and transwell migration assays, and angiogenesis by tube formation analysis. We found that CELSR1 was endogenously expressed in human umbilical vein endothelial cells (HUVEC) and HAEC. When focusing on HAEC, we found that upregulating CELSR1 expression significantly promoted cell growth, while knocking down CELSR1 inhibited the growth (p < 0.05). Using both scratch and transwell migration assays, we observed a positive correlation between CELSR1 expression and cell migratory capability. In addition, CELSR1 upregulation led to higher levels of tube formation in HAEC, while downregulating CELSR1 expression decreased tube formation (p < 0.05). Mechanistically, CELSR1-regulated migration and tube formation was mediated through disheveled segment polarity protein 3 (Dvl3). In conclusion, CELSR1 plays an important role in regulating multiple phenotypes of endothelial cells, including proliferation, migration, and formation of capillary-like structures.

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KEY WORDS: CELSR1, endothelial cells, migration, angiogenesis

DOI: 10.1134/S0006297916060055

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