Targeting the Ace2 Axis: Recombinant Ace2 Mitigates Smoke-Induced Endothelial Dysfunction and Vascular Remodeling

Background and Aims Endothelial dysfunction is a key early event in atherosclerosis, characterized by reduced nitric oxide (NO) bioavailability and imbalance in the renin–angiotensin system (RAS). Cigarette smoke exacerbates this process by increasing oxidative stress and promoting the ACE/Ang II/AT1R pathway while suppressing the protective ACE2/Ang-(1–7)/Mas axis. Recombinant ACE2 has emerged as a potential therapeutic to restore vascular homeostasis; however, its efficacy in endothelial dysfunction remains unclear. Methods A true experimental in vivo study using 25 male mice allocated into four groups: negative control, smoking control, and treatment groups receiving recombinant ACE2 at doses of 400 µg/kg and Losartan. Cigarette smoke exposure was administered for four weeks. Endothelial function was assessed via serum and tissue biomarkers (eNOS/NOS, Ang II, Ang-(1–7)) using ELISA, and vascular remodeling was evaluated by aortic intima–media thickness (IMT) through histopathology. Statistical analyses included ANOVA and Kruskal–Wallis tests. Results Cigarette smoke significantly reduced tissue NOS levels and increased IMT compared to controls (p<0.05). Recombinant ACE2 and losartan partially restored tissue NOS and reduced IMT, with significant differences observed in IMT reduction. However, no significant changes were found in serum NOS or Ang-(1–7) levels. Ang II levels showed variable responses, with partial modulation in treatment groups. Conclusion Recombinant ACE2 demonstrated protective effects against smoke-induced vascular remodeling, primarily reflected by reduced IMT, although biochemical improvements were not statistically significant. These findings suggest that recombinant ACE2 may exert structural vascular benefits through modulation of the RAS and oxidative stress pathways, potentially complementing existing therapies such as angiotensin receptor blockers.