Cyclooxygenase-2 is a critical determinant of angiotensin II-induced vascular remodeling and stiffness in resistance arteries of ouabain-treated rats

Author(s)

de Franca-Neto, Aldair ; Couto, Gisele Kruger ; Xavier, Fabiano Elias ; Rossoni, Luciana Venturini

• Document type: Journal article
• Source: Journal of Hypertension; v. 40, n. 11, p. 12-pg., 2022-11-01.

Abstract

Objective:To investigate the role of angiotensin II/AT(1) receptor signaling and/or cyclooxygenase-2 (COX-2) activation on vascular remodeling and stiffening of the mesenteric resistance arteries (MRA) of ouabain-treated rats. Methods:Ouabain-treated (OUA, 30 mu gkg/day for 5weeks) and vehicle (VEH)-treated Wistar rats were co-treated with losartan (LOS, AT(1)R antagonist), nimesulide (NIM, COX-2 inhibitor) or hydralazine hydrochloride plus hydrochlorothiazide. MRA structure and mechanics were assessed with pressure myography and histology. Picrosirius red staining was used to determine the total collagen content. Western blotting was used to detect the expression of collagen I/III, MMP-2, Src, NF kappa B, Bax, Bcl-2 and COX-2. Reactive oxygen species (ROS) and plasma angiotensin II levels were measured by fluorescence and ELISA, respectively. Results:Blockade of AT(1)R or inhibition of COX-2 prevented ouabain-induced blood pressure elevation. Plasma angiotensin II level was higher in OUA than in VEH. LOS, but not hydralazine hydrochloride with hydrochlorothiazide, prevented inward hypotrophic remodeling, increased collagen deposition and stiffness, and oxidative stress in OUA MRA. LOS prevented the reduction in the total number of nuclei in the media layer and the Bcl-2 expression induced by OUA in MRA. The higher pSrc/Src ratio, NF kappa B/I kappa B ratio, and COX-2 expression in OUA MRA were also prevented by LOS. Likewise, COX-2 inhibition prevented vascular remodeling, mechanical changes, oxidative stress and inflammation in OUA MRA. Conclusion:The results suggest that, regardless of hemodynamic adjustments, the angiotensin II/AT(1)R/pSrc/ROS/NF kappa B/COX-2 pathway is involved in the development of MRA inward hypotrophic remodeling and stiffness in ouabain-treated rats. (AU)

• FAPESP's process: 10/50048-1 - Cellular and functional bases of exercise in cardiovascular diseases
• Grantee: Carlos Eduardo Negrão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/00217-7 - Study of mechanisms involved in the remodeling of resistance arteries from ouabain hypertensive rats
• Grantee: Aldair de França Neto
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/18380-6 - Role of endogenous ouabain on vascular function and autonomic modulation in DOCA-Salt hypertensive rats
• Grantee: Luciana Venturini Rossoni
• Support Opportunities: Regular Research Grants