DP1 (Prostaglandin D₂ Receptor 1) Activation Protects Against Vascular Remodeling and Vascular Smooth Muscle Cell...

Vascular smooth muscle cell (VSMC) phenotype transition plays an essential role in vascular remodeling. PGD₂ (Prostaglandin D₂) is involved in cardiovascular inflammation. In this study, we aimed to investigates the role of DP1 (PGD₂ receptor 1) on VSMC phenotype transition in vascular remodeling after Ang II (angiotensin II) infusion in mice.

VSMC-specific DP1 knockout mice and DP1^flox/flox mice were infused with Ang II for 28 days and systolic blood pressure was measured by noninvasive tail-cuff system. The arterial samples were applied to an unbiased proteome analysis. DP1^f/f Myh11 (myosin heavy chain 11) CREERT2 R26^mTmG/+ mice were generated for VSMC lineage tracing. Multiple genetic and pharmacological approaches were used to investigate DP1-mediated signaling in phenotypic transition of VSMCs in response to Ang II administration.

DP1 knockout promoted vascular media thickness and increased systolic blood pressure after Ang II infusion by impairing Epac (exchange protein directly activated by cAMP)-1-mediated Rap-1 (Ras-related protein 1) activation. The DP1 agonist facilitated the interaction of myocardin-related transcription factor A and G-actin, which subsequently inhibited the VSMC transition to myofibroblasts through the suppression of RhoA (Ras homolog family member A)/ROCK-1 (Rho associated coiled-coil containing protein kinase 1) activity. Moreover, Epac-1 overexpression by lentivirus blocked the progression of vascular fibrosis in DP1 deficient mice in response to Ang II infusion.

Our finding revealed a protective role of DP1 in VSMC switch to myofibroblasts by impairing the phosphorylation of MRTF (myocardin-related transcription factor)-A by ROCK-1 through Epac-1/Rap-1/RhoA pathway and thus inhibited the expression of collagen I, fibronectin, ED-A (extra domain A) fibronectin, and vinculin. Thus, DP1 activation has therapeutic potential for vascular fibrosis in hypertension.