Targeting endothelial SMAD4 ameliorates endothelial dysfunction in hypertensive mice

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Hypertension Research

Background:

• Endothelial dysfunction significantly contributes to hypertension.
• TGF-β/BMP signaling pathway dysregulation worsens vascular pathogenesis.
• The specific role of SMAD4 in hypertension-related vascular inflammation and dysfunction is unclear.

Purpose of the Study:

• To investigate the role of SMAD4 in endothelial dysfunction and vascular inflammation during hypertension.
• To determine the impact of endothelial-specific SMAD4 deletion on hypertension development and vascular function.

Main Methods:

• Generated endothelial-specific Smad4 knockout (EC-Smad4 KO) mice using the Tie2-Cre/ERT2 system.
• Induced hypertension via angiotensin II (Ang II) infusion and assessed vascular function using wire myography.
• Analyzed gene expression, nitric oxide (NO), reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress markers.

Main Results:

• EC-Smad4 KO mice exhibited reduced Ang II-induced blood pressure elevation and improved endothelium-dependent relaxations.
• Ang II-induced ROS generation and VCAM1 expression were suppressed in EC-Smad4 KO mice.
• Smad4 deletion diminished p38 MAPK phosphorylation, increased p-eNOS, and reduced ER stress markers.

Conclusions:

• Smad4 signaling is a critical mediator of endothelial dysfunction and vascular inflammation in hypertension.
• Endothelial-specific Smad4 deletion ameliorates vascular dysfunction.
• This protective effect is achieved by reducing oxidative stress, ER stress, and vascular inflammation.