Mobilized Endothelial Progenitor Cells by Granulocyte-Macrophage Colony-Stimulating Factor Accelerate Reendothelialization and Reduce Vascular Inflammation After Intravascular Radiation

Abstract

Background-Endothelial progenitor cells (EPCs) play a pivotal role in repair and regeneration of damaged vessels. We investigated the role of mobilized EPCs in the healing process after intravascular radiation therapy. Methods and Results-One iliac artery of hypercholesterolemic rabbits was subjected to balloon injury and intravascular radiation with a Re-188 balloon and the contralateral iliac artery to balloon injury only. Rabbits received granulocytemacrophage colony-stimulating factor (recombinant human GM-CSF) (60 g/d subcutaneously) daily for 1 week, either 7 days before the angioplasty or at the time of angioplasty. Control rabbits received human albumin. GM-CSF significantly increased the double-positive (CD31ϩ and KDRϩ) fraction in peripheral blood monocytes and showed a higher number of EPCs than albumin after culture and, furthermore, enhanced migration and incorporation of EPCs. In the albumin group, intravascular radiation therapy reduced neointimal hyperplasia but delayed reendothelialization and aggravated monocyte infiltration. GM-CSF treatment significantly accelerated the reendothelialization and inhibited monocyte infiltration (reendothelialization index, 81Ϯ13% in the GM-CSF radiation [nϭ7] versus 30Ϯ11% in the control radiation [nϭ9] at 2 weeks, PϽ0.01). GM-CSF treatment produced an additional significant reduction in neointimal formation at 14 and 28 days after injury in the intravascular radiation groups (intima to media ratio, 0.14Ϯ0.11 in the GM-CSF radiation [nϭ5] versus 0.36Ϯ0.07 in the control radiation [nϭ5] at 4 weeks, PϽ0.01). Conclusions-GM-CSF treatment mobilizes EPCs, accelerates reendothelialization, and reduces monocytes infiltration after intravascular radiation therapy, suggesting that stem cell mobilization is a promising strategy for enhancing the vascular healing process after cytotoxic angioplasty. (Circulation. 2003;108:2918-2925.)

Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

“…One interesting possibility is that the adventitia acts as a conduit for circulating endothelial progenitor cells that are recruited after denuding injury to help restore endothelial integrity. 14,24,57 Indeed, our data also reveal that VEGF-2 expression after local gene delivery leads to significant mobilization of circulating progenitor cells, providing additional evidence for the contribution of these cells to reendothelialization.…”

Role of endothelial progenitor cells in the beneficial effects of physical exercise on atherosclerosis and coronary artery disease

“…Beside humoral factors like cytokines (6,33,77), hormones (6,11,77), chemokines (18,93), and drugs (13,49,88), exercise training has been shown to increase the number of circulating EPCs in healthy individuals and patients with CVD (2,69). In addition to influencing the amount of circulating EPCs, exercise training also has the potency to positively affect the functional capacity of EPCs.…”

Endothelial progenitor cells: Implications for cardiovascular disease

“…Stem cells within the bone marrow usually exist in a quiescent state and specific signals stimulate the stem cells to differentiate and to be mobilized into the systemic circulation. Beside humoral factors such as cytokines (51)(52)(53), hormones (51,53,54), chemokines (37,55), and drugs (56-58), exercise training (ET) has been shown to increase the number of circulating EPCs (8,9,59,60).…”