P80Kinin-mediated recruitment of regenerative circulating cells promotes endothelial healing and is dysfunctional in CAD

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Abstract

Background

Kinins derived from the vascular wall might initiate the recruitment of distinct circulating cell types which bear the B2 kinin receptor (B2R). We have investigated the role of this mechanism on endothelial healing in healthy subjects (HS) and in patients with coronary artery disease (CAD).

Methods

Expression of the B2R on peripheral blood mononuclear cell (PBMC) subsets of CAD patients and age- matched HS was assessed by flow cytometry. Adhesion to an endothelial monolayer and subsequent closure of a scratch gap, supported by paracrine effects of the adhering cells were studied in vitro. In vivo, recruitment of systemically injected cells to injured carotid endothelium, and re-endothelialization of the injured vessel were assessed in a mouse model. B2R blockade by icatibant, transplantation of B2R-deficient bone marrow cells (B2R-/- BMC), as well as adenoviral B2R overexpression were used to verify the relevance of the B2R.

Results

In HS PBMC, B2R was low expressed ( < 1000MFI) on CD14hi inflammatory monocytes and on lymphocytes, but high in angiogenic Tie2 + or KDR + monocytes and in KDR + or CXCR4 + angiogenic progenitor cells (PC) (2517 to 7516MFI; P < 0.05 vs. CD14hi). Recruitment of healthy CXCR4 + PC to endothelial cells or to the injured murine vascular wall was blocked by B2R inhibition in vitro (-67% vs. vehicle, P < 0.05) and in vivo (-58% vs. vehicle; P < 0.05), while adhesion of CD14hi monocytes was unchanged, indicating a critical role of B2R for vascular homing of CXCR4 + PCs, but not of CD14hi monocytes. In vivo endothelial healing was lower in mice receiving B2R-/- BMC than in mice receiving B2R + / + BMC (24.7% vs. 36.1%, P < 0.05). Kinin receptor expression on CXCR4 + PC (-75% vs. H; P < 0.05) and on angiogenic "early outgrowth cells" (EOC) (-68% vs. HS; P < 0.05) was reduced in CAD patients. Adhesion of CXCR4 + PC from CAD patients to endothelial cells was markedly reduced versus CXCR4 + PC of HS and not regulated by the B2R. Adenoviral B2R overexpression rescued the capacity of CAD EOC to support re-endothelialization in vivo, associated with enhanced vascular recruitment of CAD EOC after B2R overexpression.

Conclusions

We newly describe that vascular kinins do not only act via the endothelial B2R, but can also recruit endothelial-supportive circulating cells to the vessel wall via B2R on the circulating cell. The loss of B2R on angiogenic circulating cells might jeopardize the healing of endothelial injuries and thus promote the decay of endothelial function in CAD.

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