Upregulation of COX-2 and NADPH oxidase and reduced eNOS in perivascular adipose tissue are associated with resistance artery dysfunction and hypertension in naturally aged mice

Aging is a major risk factor for cardiovascular disease, with hypertension being the most common outcome. Hypertension often stems from resistance arteries endothelial dysfunction. Recent research highlights the pivotal role of perivascular adipose tissue (PVAT) in regulating endothelial function. We hypothesized that PVAT senescence contributes to vascular dysfunction and hypertension during aging. We showed that naturally aged mice developed hypertension and elevated pro-inflammatory cytokines levels. Moreover, resistance mesenteric arteries showed impaired vascular relaxation that was normalized by apocynin, an antioxidant. The vascular dysfunction was endothelium- and PVAT-dependent, and marked by: decreased NO- and COX-dependent vascular relaxation, decreased expression of endothelial nitric oxide synthase (eNOS), and increased cyclooxygenase 2 (COX-2) and NADPH oxidase subunits p22phox and gp91phox expressions in the endothelium and PVAT. Additionally, we observed that PVAT shows greater signs of senescence, particularly with higher p16 expression, indicating that PVAT is more prone to age-related cellular aging. Our findings suggest that in resistance mesenteric arteries PVAT-derived factors are crucial for triggering and amplifying vascular dysfunction in aging, leading to hypertension. The underlying mechanisms involve downregulation of eNOS-derived NO, NADPH-oxidase-dependent oxidative stress, and COX-2-derived vascular contractile factors. This research improves our understanding of the mechanisms behind age-related vascular dysfunction and associated hypertension and opens perspectives for targeted therapeutic strategies.