Vascular progenitor cells in renal and cardiovascular disease

Maintenance of endothelial integrity plays a central role in the protection against the development and progression of renal and atherosclerotic cardiovascular disease (CVD). Damaged or lost endothelial cells may be replaced through proliferation of local endothelium and by circulating bone marrow derived endothelial progenitor cells (EPC). There are also smooth muscle progenitor cells (SPC) in the blood, which may contribute to both physiological and pathological remodeling of the vascular wall. In this thesis we show that a ‘pro-atherosclerotic milieu’ in the presence of cardiovascular risk factors affects the number, function and differentiation of circulating progenitor cells. In patients with end-stage renal disease, EPC differentiation is impaired and the capacity of EPC to stimulate angiogenesis is reduced, while SPC differentiation was unaffected. Dialysis sessions induce EPC apoptosis, resulting in a temporary aggravated reduction of circulating EPC. Women with quiescent systemic lupus erythematosus (SLE) have reduced EPC levels, which may contribute to the high incidence of CVD observed in these patients. Increased apoptosis of HSC may be the underlying mechanism for the decrease in HSC-derived EPC in SLE. In diabetes, EPC levels are reduced, while SPC outgrowth is increased. The increased SPC-outgrowth is associated with increased TGF-? with decreased BMP-6 expression and aggravated neointima formation. We observed that diabetes not only negatively affects circulating angiogenic cells, but also angiogenic cells residing in the vessel wall. In obese men with the metabolic syndrome but without diabetes or manifest CVD, lower levels of circulating EPC were observed. In this thesis we propose that ‘vascular niche dysfunction’ in the bone marrow may underlie impaired endothelial progenitor cell mobilization and availability in the circulation. We show that impaired mobilization of endothelial and hematopoietic progenitor cells in diabetes is associated with dysfunction of the bone marrow stromal environment. eNOS levels in diabetic stroma were reduced and NO-inhibition impaired endothelial support of progenitor cells, suggesting a potential role for attenuated endothelial NO-release in diabetic stroma in dysfunctional progenitor cell mobilization. Impaired endothelial NO-availability occurs in various pro-atherosclerotic conditions and may be a common mechanism for reduced EPC levels. We explored pharmacological strategies to modulate EPC levels. We evaluated if treatment with PPAR-gamma agonist rosiglitazone could stimulate EPC-homing to the injured glomerulus, but although renal recovery from anti-Thy1 glomerulonephritis was improved, we did not observe a detectable increase in the number of incorporated EPC. EPC-homing involves the RANTES-chemokine, which is also an anti-atherosclerotic target because of its pro-inflammatory characteristics. We show that treatment with RANTES-inhibitor impairs ischemia-induced angiogenesis. In obese men with the metabolic syndrome, we found that intensive lipid-lowering therapy using simvastatin and ezetimibe could normalize reduced EPC-levels. Taken together, progenitor cells from the bone marrow circulate in the blood and contribute to physiological and pathophysiological vascular and renal remodeling. CVD risk factors influence the mobilization, differentiation and function of these progenitor cells. This occurs through various mechanisms, which include common pathways relevant for various CVD risk factors, and risk-factor specific mechanisms. Vascular progenitor cell levels represent a novel therapeutic target in cardiovascular and renal disease.