Angiotensin-(1-7) Prevents Angiotensin II-induced Fibrosis in Cremaster Microvessels

ObjectiveThe effect of the heptapeptide hormone Ang-(1-7) on microvascular fibrosis in rats with Ang II-induced hypertension was investigated, since vascular fibrosis/remodeling plays a prominent role in hypertension-induced end-organ damage and Ang-(1-7) inhibits vascular growth and fibrosis. MethodsFibrosis of cremaster microvessels was studied in male Lewis rats infused with Ang II and/or Ang-(1-7). ResultsAng II elevated systolic blood pressure by approximately 40mmHg, while blood pressure was not changed by Ang-(1-7). Ang II increased perivascular fibrosis surrounding 20-50m arterioles as well as interstitial fibrosis; coadministration of Ang-(1-7) prevented the increases in fibrosis. The fibrotic factor CTGF and phospho-Smad 2/3, which upregulates CTGF, were increased by Ang II; this effect was prevented by coadministration of Ang-(1-7). Although TGF- phosphorylates Smad 2/3, TGF- was no different among treatment groups. In contrast, Ang II increased the MAP kinase phospho-ERK1/2, which also phosphorylates Smad; p-ERK was reduced by Ang-(1-7). Ang-(1-7), in the presence or absence of Ang II, upregulated the MAP kinase phosphatase DUSP1. ConclusionsThese results suggest that Ang-(1-7) increases DUSP1 to reduce MAP kinase/Smad/CTGF signaling and decrease fibrosis in resistance arterioles, to attenuate end-organ damage associated with chronic hypertension.