Study On The Role Of Endothelial Progenitor Cells In The Formation And Progression Of Cerebral Aneurysm In Rats

Rationale and ObjectiveEndothelial 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.MethodsCAs were induced in male Sprague-Dawley rats and divided into 5 groups (n=20/group). Group 1:rats underwent surgery and were on a high salt diet for 1 month before sacrifice; Group 2:rats underwent surgery and were on a high salt diet for 1 month. All were treated with EPO; Group 3:rats underwent surgery and were on a high salt diet for 1 mon followed by 2 months on a normal Chow diet before sacrifice; Group 4:rats underwent surgery and were on a high salt diet for 1 mon followed by 2 months on a normal Chow diet, they were treated with EPO. Group 5: non-treatment controls. 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, and media thickness of CAs were evaluated 1 and 3 months after aneurysm induction.ResultsCirculating EPCs were significantly lower in CA rats as compared to non-surgical controls. EPO increased levels of circulating EPCs and VEGF. EPO treatment reduces the formation and progression of CA in rats. 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 associated with suppression of new CA formation and prevention of preexisting CA progression.ConclusionsWe 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 promote 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.InnovationThis is the first investigation showing that CA induction decreases the numbers of EPCs in a rat model with cerebral aneurysm. EPO treatment increases circulating EPCs and reduces the formation and progression of cerebral aneurysm. In this study, we assess the role of circulating EPCs in the formation and progression of CA. As a result, we propose a novel hypthesis on the formation and progression of CA.