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.

Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy

“…For the determination of cardiomyocyte hypertrophy in the non-infarcted region in hearts 45 days postoperation, heart tissue was fixed in 4% paraformaldehyde, embedded in paraffin, and cut into 7-m sections. After incubation with tetramethylrhodamine isothiocyanate-labeled wheat germ agglutinin (1:200), as previously described (62,65), the wheat germ agglutinin-stained sections were then counterstained with DAPI. The images were acquired and analyzed using Image Pro Plus software to calculate myocardial cross-sectional area.…”

“…Long-term LV functional analysis. Two-dimensional (2D) echocardiographic measurements were performed on postoperation day 45, as previously described (36,62). The rats were anesthetized, and transthoracic echocardiography of the LV was performed (Vivid7, GE Medical System, Horton, Norway).…”

The inextricable role of the kidney in hypertension

“…However, preclinical models predict that reduced levels of VEGF-C would promote hypertension. Consistent with this notion, a recent report showed that overexpression of VEGF-C lowered blood pressure in a model of salt-sensitive hypertension, whereas blocking VEGF-C activity exaggerated the severity of hypertension (55). Nonetheless, chronic hypertension in humans is a complex disorder; it is possible that the observed elevation in VEGF-C levels may reflect tissue resistance to VEGF-C or even a compensatory response.…”

Immune cell trafficking, lymphatics and hypertension

“…In another study, TonEBP‐mediated cardiac lymphangiogenesis and macrophage infiltration was observed in the left ventricles of SHRs that were fed a high‐salt diet (Yang et al ., ; Yang et al ., ). Retrovirus‐induced overexpression of VEGFC led to enhanced lymphangiogenesis, reduced myocardial fibrosis and macrophage infiltration, decreased BP and preserved myocardial function.…”