Small artery remodeling and stiffening in deoxycorticosterone acetate-salt hypertensive rats involves the interaction between endogenous ouabain/Na⁺K⁺-ATPase/cSrc signaling

Author(s)

Tomazelli, Caroline Aparecida ; Ishikawa, Flavia Midori ; Couto, Gisele Kruger ; Parente, Juliana Montenegro ; de Castro, Michele Mazzaron ; Xavier, Fabiano Elias ; Rossoni, Luciana Venturini

• Document type: Journal article
• Source: Journal of Hypertension; v. 41, n. 10, p. 11-pg., 2023-10-01.

Abstract

Objective: Endogenous ouabain (EO) increases in some patients with hypertension and in rats with volumedependent hypertension. When ouabain binds to N+ K+ -ATPase, cSrc is activated, which leads to multieffector signaling activation and high blood pressure (BP). In mesenteric resistance arteries (MRA) from deoxycorticosterone acetate (DOCA)-salt rats, we have demonstrated that the EO antagonist rostafuroxin blocks downstream cSrc activation, enhancing endothelial function and lowering oxidative stress and BP. Here, we examined the possibility that EO is involved in the structural and mechanical alterations that occur in MRA from DOCA-salt rats. Methods: MRA were taken from control, vehicle-treated DOCA-salt or rostafuroxin (1 mg/kg per day, for 3 weeks)-treated DOCA-salt rats. Pressure myography and histology were used to evaluate the mechanics and structure of the MRA, and western blotting to assess protein expression. Results: DOCA-salt MRA exhibited signs of inward hypertrophic remodeling and increased stiffness, with a higher wall:lumen ratio, which were reduced by rostafuroxin treatment. The enhanced type I collagen, TGFb1, pSmad2/3(Ser465/457)/Smad2/3 ratio, CTGF, p-Src(Tyr418), EGFR, c-Raf, ERK1/2 and p38MAPK protein expression in DOCA-salt MRA were all recovered by rostafuroxin. Conclusion: A process combining Na+ K+ -ATPase/cSrc/ EGFR/Raf/ERK1/2/p38MAPK activation and a Na+ K+ -ATPase/cSrc/TGF-1/Smad2/3/CTGF-dependent mechanism explains how EO contributes to small artery inward hypertrophic remodeling and stiffening in DOCA-salt rats. This result supports the significance of EO as a key mediator for end-organ damage in volume-dependent hypertension and the efficacy of rostafuroxin in avoiding remodeling and stiffening of small arteries. (AU)

• FAPESP's process: 19/08026-5 - Adaptations on perivascular innervation and remodeling in resistance arteries of DOCA-salt hypertension model: the role of endogenous ouabain
• Grantee: Luciana Venturini Rossoni
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/18828-3 - Effects of cross-fostering on mechanical and structural adjustments of mesenteric resistance arteries from hypertensive and normotensive rats
• Grantee: Flávia Midori Ishikawa
• Support Opportunities: Scholarships in Brazil - Scientific Initiation