ERYTHROPOIETIN INCREASES CIRCULATING ENDOTHELIAL PROGENITOR CELLS AND REDUCES THE FORMATION AND PROGRESSION OF CEREBRAL ANEURYSM IN RATS

Endothelial dysfunction triggers early pathological changes in vessel walls, potentially leading to the formation of cerebral aneurysm (CA). Endothelial progenitor cells (EPCs) are critical in repairing damaged endothelium and could prevent or slow CA formation. We hypothesize that erythropoietin (EPO) stimulates EPCs mobilization, could alter the rate of CA formation and progression. The hypothesis was tested in a rat model of CA. CAs were induced in male Sprague-Dawley rats and treated with s.c. administration of EPO. Circulating EPCs and serum vascular endothelial grow factor (VEGF) were measured be flow cytometry and ELISA, respectively. mRNAs for inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), matrix metalloproteinase-2 (MMP-2), and MMP-9 in aneurysm tissue were quantified by Real-time PCR. The size, internal elastic lamina (IEL), and media thickness of CAs were evaluated 1 and 3 months after aneurysm induction. Circulating EPCs were significantly lower in CA rats as compared to nonsurgical controls. EPO increased levels of circulating EPCs and VEGF. It also decreased iNOS, MMP-2, and MMP-9 mRNA levels, while increased eNOS mRNA in aneurysm tissue. The changes in EPCs and biochemical markers are associated with suppression of new CA formation and prevention of preexisting CA progression. We have shown a close association among circulating EPCs, biochemical markers related to vascular remodeling, and the rate of CA formation and progression. Changes in patterns of cerebral blood flow and hypertension induced by surgical ligations of selected arteries exert significant hemodynamic stress to weaken vessel walls, primarily at sites of basilar bifurcation. The surgical stress also reduced circulating EPCs and slowed vascular repairs. EPO mobilizes EPCs from the bone marrow and promotes their homing. These results suggest that EPCs may serve as a marker for CA progression and EPO a promising candidate for the clinical management of CA. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.