Spatiotemporal EP4-fibulin-1 expression is associated with vascular intimal hyperplasia.

Area of Science:

• Vascular Biology
• Molecular Medicine
• Cardiovascular Research

Background:

• Cyclooxygenase-2-derived prostaglandin E2 (PGE2) is implicated in vascular intimal hyperplasia (IH).
• EP4 receptor signaling in vascular smooth muscle cells (VSMCs) is known to promote IH, while its role in endothelial cells is protective.
• The precise role and spatiotemporal expression of EP4 in IH remain to be fully elucidated.

Purpose of the Study:

• To investigate the spatiotemporal expression of the EP4 receptor in injured vessels.
• To determine the role of EP4 signaling in VSMCs in the development of vascular intimal hyperplasia.
• To explore EP4's downstream signaling pathways and assess EP4 modulation as a therapeutic strategy for IH.

Main Methods:

• Generation of EP4 reporter mice (Ptger4-IRES-nlsLacZ) to track EP4 expression.
• Utilized VSMC-specific EP4 knockout (Ptger4fl/+;SM22-Cre) and overexpression (Ptger4-Tg) mouse models.
• Investigated downstream signaling involving fibulin-1 (Fbln1) and extracellular matrix protein 1 (ECM1) using genetic manipulation and recombinant proteins.
• Administered systemic EP4 antagonist in wild-type mice following vascular injury.

Main Results:

• EP4 expression was transiently upregulated in VSMCs within the neointima after femoral artery wire injury.
• VSMC-specific EP4 deficiency reduced IH, whereas overexpression exacerbated it.
• EP4 stimulation increased fibulin-1 expression in VSMCs, which, along with ECM1, promoted VSMC proliferation and migration via TGF-β/Smad3 signaling.
• Targeting fibulin-1 in VSMCs attenuated IH, and systemic EP4 antagonism reduced injury-induced IH.

Conclusions:

• EP4 signaling in VSMCs is a key driver of vascular intimal hyperplasia, partly mediated by fibulin-1.
• Modulating EP4 activity, potentially through antagonism, represents a promising therapeutic avenue for treating IH.