Prostaglandin I₂ (PGI₂) Signaling Attenuates Hypertension And Associated Vascular Inflammation

In recent years, inflammation was determined to play a causal role in hypertension. Interestingly, evidence suggests that long-lasting use of cyclooxygenase inhibitors, which prevent metabolism of arachidonic acid (AA) to prostaglandins and thromboxane, increases blood pressure. Prostaglandin I 2 (PGI 2 ) is an AA metabolite that has immunomodulatory effects. Our group has demonstrated that PGI 2 acts to directly inhibit the functionality of pro-inflammatory DCs and CD4+ Th1 and Th2 cells, while promoting the function of tolerogenic DCs and T regulatory cells (Treg). Further, mice deficient in the receptor for PGI 2 , IP, develop elevated blood pressure in response to high salt diet, suggesting that PGI 2 signaling is important for controlling blood pressure elevation in response to stimuli. These studies led us to hypothesize that PGI 2 signaling attenuates hypertension and associated vascular inflammation. We found that infusion of the PGI 2 analog, treprostinil (TPL), into mice resulted in blunted blood pressure following 4 weeks of angiotensin II (Ang II) infusion (490ng/kg/min) compared to mice that received Ang II and TPL vehicle (42.8 mmHg reduction, p<0.05). Concomitantly, TPL prevented Ang II-induced vascular infiltration of CD3+ T cells (0.98 x10 3 compared to 2.04x10 3 cells/aorta, p<0.05) and CD11c+MHCII+ cells (0.59 x10 3 compared to 1.95x10 3 cells/aorta, p<0.0001). Further, IP deficient mice (IP KO) had elevated blood pressure compared to wild-type (WT) mice in response to low dose Ang II (150ng/kg/mg) (19.9 mmHg elevation, p<0.05). IP KO mice also had increased infiltration of vascular CD3+ T cells (2.42x10 3 compared to 1.36x10 3 cells/aorta p<0.05) and a trend toward increased CD11c+MHCII+ cells compared to WT mice. These studies demonstrate that understanding the mechanisms through which PGI 2 augments the immune response associated with hypertension may shed new insight into potential therapeutics.