title: Overexpression of VEGF-C attenuates chronic high salt intake-induced left ventricular maladaptive remodeling in spontaneously hypertensive rats.
abstract: Recent studies have shown that the tonicity-responsive enhancer binding protein (TonEBP)/vascular endothelial growth factor-C (VEGF-C) signaling pathway-induced lymphangiogenesis provides a buffering mechanism for high salt (HS) intake-induced elevation of blood pressure (BP). Moreover, blocking of TonEBP/VEGF-C signaling by mononuclear phagocyte depletion can induce salt-sensitive hypertension in rats. We hypothesized that HS intake could have an impact on cardiac lymphangiogenesis, and regulation of VEGF-C bioactivity, which is largely through the main receptor for VEGFR-3, may modulate HS intake-induced left ventricular remodeling. We demonstrated upregulation of TonEBP, increased macrophage infiltration, and enhanced lymphangiogenesis in the left ventricles of spontaneously hypertensive rats (SHR) that were fed a HS diet (8.0% NaCl). Then, retrovirus vectors capable of overexpression (ΔNΔC/VEGF-C/Cys152Ser, used for overexpressing VEGF-C) and blocking (VEGFR-3-Rg, used for trapping of bioactive VEGF-C) of VEGF-C and control vector (pLPCX) were intravenously administered to SHR from week 9 of a 12-wk HS loading period. At the end of the HS challenge, overexpression of VEGF-C led to enhanced cardiac lymphangiogenesis, decreased myocardial fibrosis, and macrophage infiltration, preserved left ventricular functions, as well as decreased blood pressure level compared with the HS group and the control vector-treated HS group. In contrast, systemic blocking of VEGF-C was associated with elevation of blood pressure level and an exacerbation of hypertensive left ventricular remodeling, as indicated by increased fibrosis and macrophage infiltration, and diminished lymphangiogenesis. Hence, our findings highlight that VEGF-C/VEGFR-3 is a promising therapeutic target to attenuate hypertensive left ventricular remodeling induced by HS intake, presumably via blood pressure-dependent and -independent mechanisms.
authors: Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Institute of Cardiovascular Disease and Heart Center, Pingjin Hospital, Logistics University of the Chinese People's Armed Police Forces, Tianjin, China; and.
authors: Guo-Hong
authors: GH
authors: Yang
authors: Xin
authors: X
authors: Zhou
authors: Wen-Jie
authors: WJ
authors: Ji
authors: Shan
authors: S
authors: Zeng
authors: Yan
authors: Y
authors: Dong
authors: Lu
authors: L
authors: Tian
authors: Ying
authors: Y
authors: Bi
authors: Zhao-Zeng
authors: ZZ
authors: Guo
authors: Fei
authors: F
authors: Gao
authors: Hong
authors: H
authors: Chen
authors: Tie-Min
authors: TM
authors: Jiang
authors: Yu-Ming
authors: YM
authors: Li
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D006321:Heart / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D042583:Lymphangiogenesis / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D012982:Sodium, Dietary / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D012982:Sodium, Dietary; D042582:Vascular Endothelial Growth Factor C
keywords: VEGF-C; VEGFR-3; hypertension; left ventricular remodeling; lymphangiogenesis