Abstract 16896: Kinin-Mediated Recruitment of Circulating Endothelial Supporting Cells is Impaired in Patients with CAD or Diabetes: Impact on Endothelial Healing
Purpose: We have investigated the role of vascular-derived kinins for the recruitment of angiogenic monocytes and circulating angiogenic progenitor cells (CPC) to the vessel wall, and the functionality of this mechanism during coronary artery disease (CAD) and type 2 diabetes mellitus (T2D).
Methods: Expression of the kinin B2 receptor (B2R) on peripheral blood mononuclear cell (PBMC) subsets of CAD patients with or without T2D, and age- matched healthy subjects (HS) was assessed by flow cytometry. Adhesion to an endothelial monolayer and subsequent healing of a scratch gap in the endothelium was studied in vitro. In vivo, recruitment of systemically injected human PBMC to injured carotid endothelium was assessed in a mouse model. B2R blockade by icatibant or B2R deficient bone marrow cells (B2R-/- BMC) were used in those analyses to verify the relevance of the B2R.
Results: In HS PBMC, B2R was low expressed (<1000MFI) on CD14hi inflammatory monocytes and highest in angiogenic Tie2+ or KDR+ monocytes and in KDR+ or CXCR4+ angiogenic CPCs (2517 to 7516MFI; P<0.05 vs. CD14hi). Recruitment of healthy CXCR4+ CPC to the endothelium 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 CPCs, but not of CD14hi monocytes. Kinin receptor expression on CXCR4+ PC was reduced in CAD patients with or without T2D (-75% vs. H; P<0.05). Endothelial recruitment of CXCR4+ PC from T2D patients was markedly impaired and not regulated by the B2R. In vitro, endothelial gap closure was, partially mediated by the B2R during adhesion of healthy PBMC, which was lost in patients with T2D PBMC. Adenoviral B2R overexpression increased in vitro endothelial healing, while silencing of B2R abolished the recruitment and acceleration of gap closure by healthy CPC. In vivo endothelial healing was impaired in B2R-/- derived BMC that were transplanted in mice with endothelial injury (24.7% vs. 36.1%, P<0.05).
Conclusions: We newly describe that vascular kinins recruit endothelial-supportive circulating cells to the vessel wall via B2R on the circulating cell. The loss of B2R on those cells might contribute to the loss of endothelial function in T2D.
- © 2011 by American Heart Association, Inc.