Toll-like receptor 9 contributes to perivascular adipose tissue dysfunction in spontaneously hypertensive rats

Abstract

Perivascular adipose tissue (PVAT) plays a key role in vascular homeostasis by exerting anticontractile effects. However, PVAT dysfunction in hypertension contributes to vascular abnormalities via inflammation and oxidative stress. This study investigates the role of Toll-like receptor 9 (TLR9) in PVAT dysfunction in spontaneously hypertensive rats (SHR). Elevated TLR9 expression and activation were observed in SHR PVAT, along with increased pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and reactive oxygen species (ROS). These changes impaired PVAT's anticontractile effects, reduced nitric oxide (NO) bioavailability, and heightened vascular contraction. Pharmacological inhibition of TLR9 with ODN2088 restored PVAT's anticontractile function, reduced inflammation and oxidative stress, and improved vascular tone. This treatment also significantly lowered systolic blood pressure in SHR. TLR9-mediated PVAT dysfunction was closely linked to NF-κB signaling, as inhibition of this pathway attenuated inflammatory cytokine production and improved vascular reactivity. ROS scavenging with Tiron confirmed the role of oxidative stress in the loss of PVAT function. Despite unaltered endothelial nitric oxide synthase (eNOS) expression, NO levels were reduced in SHR PVAT due to ROS-induced scavenging. Notably, TLR9 inhibition restored NO bioavailability, reinforcing its therapeutic potential. These findings establish TLR9 as a critical mediator of PVAT dysfunction in hypertension, driving inflammation, oxidative stress, and vascular impairment. Targeting TLR9 and oxidative stress may represent effective therapeutic strategies for mitigating vascular dysfunction in hypertension.

Keywords: Hypertension; Inflammation; Oxidative stress; Perivascular adipose tissue; Toll-like receptor 9.