Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage - A new paradigm in glitazone pleiotropy

Article

关键词: SMOOTH-MUSCLE-CELLS;    GROWTH-FACTOR;    PPAR-GAMMA;    IN-VITRO;    RECEPTOR;    TROGLITAZONE;    EXPRESSION;    TRANSDIFFERENTIATION;    ATHEROSCLEROSIS;    PROSTAGLANDINS;   

DOI  :  10.1161/01.CIR.0000123231.49594.21

来源: SCIE

【 摘 要 】

Background - Peroxisome proliferator - activated receptor-gamma (PPAR-gamma) agonists inhibit vascular smooth muscle proliferation and migration and improve endothelial function. It is unknown whether PPAR-gamma agonists favorably modulate bone marrow ( BM) - derived angiogenic progenitor cells (APCs) to promote endothelial lineage differentiation and early reendothelialization after vascular intervention. Methods and Results - C57/BL6 mice, treated with or without rosiglitazone ( 8 mg/kg per day), a PPAR-gamma agonist, underwent femoral angioplasty. Rosiglitazone treatment attenuated neointimal formation (intima/media ratio: 0.98 +/- 0.12 [ rosiglitazone] versus 3.1 +/- 0.5 [ control]; P < 0.001; n = 10 per group). Using a BM transplantation model, we identified that 58 +/- 12% of the cells within the neointima at 4 weeks were derived from the BM. Pure endothelial marker - positive, pure alpha-smooth muscle actin (alpha SMA) - positive, or double-positive APCs could be found both in mouse BM and in human peripheral blood after culture in conditional medium enriched with vascular endothelial growth factor. Rosiglitazone caused a 6-fold ( P < 0.001) increase in colony formation by human endothelial progenitor cells, promoted the differentiation of APCs toward the endothelial lineage in mouse BM in vivo ( 0.66 +/- 0.06% [ control] to 0.95 +/- 0.08% [ rosiglitazone]; P < 0.05) and in human peripheral blood in vitro ( 13.2 +/- 1.5% [ control] to 28.4 +/- 3.3% [ rosiglitazone]; P < 0.05), and inhibited the differentiation toward the smooth muscle cell lineage. Within the neointima, rosiglitazone also stimulated APCs to differentiate into mature endothelial cells and caused earlier reendothelialization compared with controls ( 31 +/- 5 versus 8 +/- 2 CD31-positive cells per millimeter of neointimal surface on day 14; P < 0.01). Conclusions - Similar to embryonic stem cell - derived progenitors, the adult BM and peripheral blood harbor APCs that are at least bipotential and able to differentiate into endothelial and smooth muscle lineages. The PPAR-gamma agonist rosiglitazone promotes the differentiation of these APCs toward the endothelial lineage and attenuates restenosis after angioplasty.

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