Disruption of endothelial peroxisome proliferator-activated receptor-gamma reduces vascular nitric oxide production

Area of Science:

• Vascular biology
• Molecular medicine
• Endocrinology

Background:

• Vascular endothelial cells express peroxisome proliferator-activated receptor-gamma (PPARgamma), a transcription factor involved in metabolism, proliferation, and inflammation.
• PPARgamma ligands improve endothelial function, while mutations impair it, suggesting a role in nitric oxide (NO) production.

Purpose of the Study:

• To investigate the role of endothelial PPARgamma in regulating vascular nitric oxide production in vivo.
• To determine if endothelial PPARgamma deficiency leads to endothelial dysfunction.

Main Methods:

• Generated endothelial-specific PPARgamma knockout mice (ePPARgamma(-/-)) by crossing endothelial Cre mice with floxed PPARgamma mice.
• Assessed blood pressure, aortic ring relaxation responses to acetylcholine and sodium nitroprusside, and nitric oxide release in ePPARgamma(-/-) and control mice.
• Measured oxidative stress markers and nuclear factor-kappaB (NF-κB) activation in aortic tissues.

Main Results:

• ePPARgamma(-/-) mice exhibited baseline hypertension and similar blood pressure responses to angiotensin II compared to controls.
• Aortic ring relaxation to acetylcholine was impaired in ePPARgamma(-/-) mice, while responses to sodium nitroprusside were unaffected.
• Intact aortic segments from ePPARgamma(-/-) mice showed reduced nitric oxide production, increased oxidative stress, and elevated NF-κB activation, despite similar endothelial nitric oxide synthase (eNOS) expression.

Conclusions:

• Endothelial PPARgamma is a key regulator of vascular nitric oxide production.
• Disruption of endothelial PPARgamma leads to hypertension and endothelial dysfunction in vivo.
• Reduced NO bioavailability in ePPARgamma(-/-) mice is linked to oxidative stress and NF-κB activation.