Hypertension in mice lacking the CXCR3 chemokine receptor

Area of Science:

• Cardiovascular Biology
• Immunology
• Renal Physiology

Background:

• CXC chemokine receptor 3 (CXCR3) is implicated in inflammatory diseases and allograft rejection.
• Its role in physiological vascular function and hypertension is not well understood.
• CXCR3 is expressed on vascular endothelial and smooth muscle cells.

Purpose of the Study:

• To investigate the role of CXCR3 in regulating vascular contractility and blood pressure.
• To elucidate the molecular mechanisms underlying CXCR3's influence on vascular function.

Main Methods:

• Utilized CXCR3 knockout (CXCR3-/-) mice and wild-type littermates.
• Measured mean arterial pressure in vivo.
• Assessed isolated resistance vessel contractility and vasodilatation responses to angiotensin II (ANG II) and acetylcholine (ACh).
• Quantified expression of ANG II type 1 receptor (AT1R) and M3-acetylcholine receptor (M3-AChR) via molecular assays.
• Investigated transcription factor interactions with the AT1R promoter using electrophoretic mobility shift assays (EMSA).

Main Results:

• CXCR3-/- mice exhibited elevated mean arterial pressures.
• Vascular smooth muscle cells from CXCR3-/- mice showed increased contractility to ANG II and reduced vasodilatation to ACh.
• These functional changes correlated with higher AT1R expression and lower M3-AChR expression in mesenteric arteries.
• EMSA studies revealed SP-1 and EGR-1 complex formation with the AT1R promoter.
• Increased SP-1 expression in CXCR3-/- mice suggested an imbalanced transcription factor complex, leading to upregulated AT1R and hypertension.

Conclusions:

• CXCR3 plays a critical role in maintaining normal vascular contractility and blood pressure regulation.
• Disruption of CXCR3 leads to hypertension, likely mediated by increased AT1R expression.
• CXCR3 signaling influences vascular tone through modulation of AT1R and M3-AChR pathways.