Hyperhomocysteinemia suppresses bone marrow CD34+/VEGF receptor 2+ cells and inhibits progenitor cell mobilization and homing to injured vasculature—a role of β1‐integrin in progenitor cell migration and adhesion. Issue 7 (8th April 2015) - Nelson, Jun
ABSTRACT: Hyperhomocysteinemia (HHcy) impairs re‐endothelialization and accelerates vascular remodeling. The role of CD34 + /VEGF receptor (VEGFR) 2 + progenitor cells (PCs) in vascular repair in HHcy is unknown. We studied the effect of HHcy on PCs and its role in vascular repair in severe HHcy (~150 μM), which was induced in cystathionine‐β synthase heterozygous mice fed a high‐methionine diet for 8 weeks. Vascular injury was introduced by carotid air‐dry endothelium denudation. CD34 + /VEGFR2 + cells were examined by flow cytometry. HHcy reduced bone marrow (BM) CD34 + /VEGFR2 + cells and suppressed replenishment of postinjury CD34 + /VEGFR2 + cells in peripheral blood (PB). Donor green fluorescent protein‐positive PC homing to the injured vessel was reduced in HHcy after CD34 + PCs from enhanced green fluorescent protein mice were adoptively transferred following carotid injury. CD34 + PC transfusion partially reversed HHcy‐suppressed re‐endothelialization and HHcy‐induced neointimal formation. Furthermore, homocysteine (Hcy) inhibited proliferation, adhesion, and migration and suppressed β1‐integrin expression and activity in human CD34 + endothelial colony‐forming cells (ECFCs) isolated from PBs in a dose‐dependent manner. A functional‐activating β1‐integrin antibody rescued Hcy‐suppressed adhesion and migration in CD34 + ECFCs. In conclusion, HHcy reduces BM CD34 + /VEGFR2 + generation and suppresses CD34 + /VEGFR2 + cell mobilization and homing to the injured vessel via β1‐integrin inhibition, which partially contributes to impaired re‐endothelialization and vascular remodeling.—Nelson, J., Wu, Y., Jiang, X., Berretta, R., Houser, S., Choi, E., Wang, J., Huang, J., Yang, X., Wang, H. Hyperhomocysteinemia suppresses bone marrow CD34 + /VEGF receptor 2 + cells and inhibits progenitor cell mobilization and homing to injured vasculature—a role of β1‐integrin in progenitor cell migration and adhesion. FASEB J . 29, 3085‐3099 (2015). www.fasebj.org