Endothelial FGF receptor signaling accelerates atherosclerosis

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Atherosclerosis Research

Background:

• Fibroblast growth factors (FGFs) promote angiogenesis, aiding ischemic disease treatment.
• The role of endothelial FGF receptors (FGF-Rs) in atherosclerosis is not well understood.

Purpose of the Study:

• To investigate the impact of endothelial FGF-R2 signaling on atherosclerosis development.
• To elucidate the molecular mechanisms by which FGF-R2 influences endothelial cell function in atherosclerosis.

Main Methods:

• Generated endothelial cell-specific FGF-R2 overexpressing mice (Tie2-FGF-R2-Tg).
• Crossed these mice with apolipoprotein E-deficient (ApoE-KO) mice to create Tie2-FGF-R2-Tg/ApoE-KO mice.
• Fed mice a Western diet and analyzed atherosclerotic lesion area, endothelial cell markers, and vascular smooth muscle cell proliferation.

Main Results:

• Tie2-FGF-R2-Tg/ApoE-KO mice showed a 2.0-fold increase in atherosclerotic lesion area compared to ApoE-KO controls.
• FGF-R2 overexpression elevated p21(Cip1) levels, increased VCAM-1 and ICAM-1 expression, accelerated apoptosis, and reduced EC proliferation.
• Knockdown of p21(Cip1) normalized these endothelial cell dysfunctions.
• Increased expression of PDGF-B and Egr-1 was observed in the aortic endothelium.
• Vascular smooth muscle cell proliferation was significantly higher in Tie2-FGF-R2-Tg/ApoE-KO mice.

Conclusions:

• Endothelial FGF-R2 signaling exacerbates atherosclerosis.
• The mechanism involves p21(Cip1)-mediated endothelial cell dysfunction.
• Therapeutic angiogenesis using FGF in atherosclerotic patients warrants caution.