Hypertension in mice lacking the CXCR3 chemokine receptor

Abstract

The CXC chemokine receptor 3 (CXCR3) has been linked to autoimmune and inflammatory disease, allograft rejection, and ischemic nephropathy. CXCR3 is expressed on endothelial and smooth muscle cells. Although a recent study posited that antagonizing of CXCR3 function may reduce atherosclerosis, the role of CXCR3 in controlling physiological vascular functions remains unclear. This study demonstrates that disruption of CXCR3 leads to elevated mean arterial pressures in anesthetized and conscious mice, respectively. Stimulation of isolated resistance vessels with various vasoconstrictors showed increased contractibility in CXCR3-/- mice in response to angiotensin II (ANG II) and a decreased vasodilatation in response to acetylcholine (ACh). The increased contractibility was related to higher ANG II type 1 receptor (AT1R) expression, whereas the decreased vasodilatation was related to lower M3-ACh receptor expression in the mesenteric arteries of CXCR3-/- mice compared with wild-type mice. The vasodilatatory response to ACh could be antagonized by the nonselective ACh receptor antagonist atropine and the selective M3 receptor antagonist 4-DAMP, but not by M1, M2, and M4 receptor antagonists. Additionally, EMSA studies revealed that transcription factors SP-1 and EGR-1 interact as a complex with the murine AT1R promoter region. Furthermore, we could show increased expression of SP-1 in CXCR3-/- mice indicating an imbalanced SP-1 and EGR-1 complex formation which causes increased AT1R expression and hypertension. The data indicate that CXCR3 receptor is important in vascular contractility and hypertension, possibly through upregulated AT1R expression.

Role of M1, M3, and M5 muscarinic acetylcholine receptors in cholinergic dilation of small arteries studied with gene-targeted mice

“…For example, in vivo studies in normo-and hypertensive humans employing receptor subtype-preferring antagonists suggested that cholinergic vasodilation in forearm resistance vessels is mainly mediated by M 3 receptors (5-6). Similar results have been obtained in pharmacological studies in rat isolated perfused kidneys and in mesenteric vascular preparations from rats and mice (14,(21)(22)(23). Other classical pharmacological studies in the cat middle cerebral artery and in mouse pial arterioles also suggested that M 3 receptors are responsible for cholinergic vasorelaxation in the cerebral circulation (11,38).…”

The role of chemokines in hypertension and consequent target organ damage

“…For example, CXCR3-deficient mice exhibit elevated baseline blood pressure, enhanced ex vivo vasoconstriction in response to Ang II, and blunted endothelium-dependent vasodilation compared to wild-type controls (66). These characteristics may be related to augmented AT 1 receptor expression in the vasculature.…”

“…Following antigen experience, CD8 + T cells lacking CXCR3 preferentially differentiate into memory cells, not short-lived effector cells, thus amplifying the memory pool. CD8 + memory T cells have been implicated in hypertension (87), and augmented memory T cell pools may explain why CXCR3-deficient mice experience exacerbated hypertensive pathology (66). Recent work also highlights the ability of T cells to trans-differentiate between subsets at sites of inflammation (88).…”

Sex differences in primary hypertension

“…Unfortunately, blood pressure has only been reported for males in hypertensive mice lacking atrial natriuretic factor, which leads to salt-sensitive hypertension [77] and mice lacking the atrial natriuretic type A receptor, which are hypertensive but not salt-sensitive [78]. Further missed opportunities for understanding sex differences in hypertension include mice lacking the CXC chemokine receptor 3 [79] and 11β-hydroxysteroid dehydrogenase type 2 [80] since only male blood pressure has been reported thus far.…”