title: Vasopressin V1Areceptor mediates cell proliferation through GRK2-EGFR-ERK1/2pathway in A7r5 cells.
abstract: Abnormal proliferation and hypertrophy of vascular smooth muscle (VSMC), as the main structural component of the vasculature, is an important pathological mechanism of hypertension. Recently, increased levels of arginine vasopressin (AVP) and copeptin, the C-terminal fragment of provasopressin, have been shown to correlate with the development of preeclampsia. AVP targets on the Gq-coupled vasopressin V1Areceptor and the Gs-coupled V2receptor in VSMC and the kidneys to regulate vascular tone and water homeostasis. However, the role of the vasopressin receptor on VSM cell proliferation during vascular remodeling is unclear. Here, we studied the effects of AVP on the proliferation of the rat VSMC-derived A7r5 cells. AVP, in a time- and concentration-dependent manner, promoted A7r5 cell proliferation as indicated by the induction of proliferating cell nuclear antigen expression, methylthiazolyldiphenyl-tetrazolium reduction and incorporation of 5'-bromodeoxyuridine into cellular DNA. These effects, coupled with the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), were blocked by a V1Areceptor antagonist SR45059 but not by a V2receptor antagonist lixivaptan. Although acute activation of V1Areceptor induced ERK1/2phosphorylation via a protein kinase C-dependent pathway, this effect was not involved in cell proliferation. Cell proliferation and ERK1/2phosphorylation in response to prolonged stimulation with AVP were abolished by inhibition of G protein-coupled receptor kinase 2 (GRK2) and epidermal growth factor receptor (EGFR) using specific inhibitors or small hairpin RNA knock-down. These results suggest that activation of V1A, but not V2receptor, produces a cell proliferative signal in A7r5 cells via a GRK2/EGFR/ERK1/2-dependent mechanism.
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China.
authors: Lingling
authors: L
authors: Zhang
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China.
authors: Xiaojun
authors: X
authors: Wang
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China.
authors: Hong
authors: H
authors: Cao
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China.
authors: Yunxuan
authors: Y
authors: Chen
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China.
authors: Xianfan
authors: X
authors: Chen
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China.
authors: Xi
authors: X
authors: Zhao
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China.
authors: Feifei
authors: F
authors: Xu
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China.
authors: Yifan
authors: Y
authors: Wang
authors: Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors: Anthony Yiu-Ho
authors: AY
authors: Woo
authors: Cardiovascular laboratory, Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, China. Electronic address: Zhuwz@ntu.edu.cn.
authors: Weizhong
authors: W
authors: Zhu
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017483:Receptors, Vasopressin / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D005419:Flavonoids; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D066246:ErbB Receptors; D011493:Protein Kinase C; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Arginine vasopressin; Cell proliferation; ERK(1/2); G-protein coupled receptor kinase; PKC; Vascular smooth muscle