Formation of new blood vessels during gastric ulcer healing. Role of bone marrow derived endothelial progenitor cells.

ABSTRACT

Regeneration of blood vessels (neovascularization) is critical for gastric ulcer (GU) healing. The contributions of bone marrow-derived endothelial progenitor cells (BMD-EPCs) to neovascularization during GU healing are not fully elucidated. Our specific aims were to determine whether in GU, BMD-EPCs are incorporated into blood vessels of GU granulation tissue jointly with ECs, thus forming hybrid vessels; or, form separate vessels consisting of only BMD-EPCs. GUs were induced in rats by serosal application of acetic acid. Vascular cast studies were performed at 7, 21 and 60 days after GU induction and tissue specimens were immunostained for CD34, CD133, VEGFR2, and SDF-1 at 14 days. Human relevance was determined using archival human GU specimens. In rat GU granulation tissue BMD-EPCs constituted 28 ± 3% of all cells lining newly formed blood vessels, and were nested between fully differentiated ECs. In rat GU granulation tissue, expression of stromal derived factor-1 (SDF-1) - the major chemoattractant for BMD-EPCs was strongly upregulated. In human GU specimens, BMD-EPCs were also present in granulation tissue constituting 34 ± 3% of all cells lining blood vessels and jointly formed hybrid vessels with differentiated ECs. Our study uncovered that BMD-EPCs incorporate into newly formed blood vessels in GU granulation tissue; and, together with ECs of pre-existing vessels, contribute to and support neovascularization through vasculogenesis. This study is the first demonstration that vasculogenesis occurs during GU healing in both humans and in rats.