Background-Myocardial ischemia provides a potent stimulus to angiogenesis, and the mobilization and differentiation of endothelial progenitor cells (EPCs) has been shown to be important in this process. An elevated level of C-reactive protein (CRP) has emerged as one of the most powerful predictors of cardiovascular disease. However, the impact of CRP on EPC biology is unknown. Methods and Results-EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in endothelial cell basal medium-2 in the absence and presence of CRP (5 to 20 g/mL), rosiglitazone (1 mol/L), and/or vascular endothelial growth factor. EPC differentiation, survival, and function were assayed. CRP at concentrations Ն15 g/mL significantly reduced EPC cell number, inhibited the expression of the endothelial cell-specific markers Tie-2, EC-lectin, and VE-cadherin, significantly increased EPC apoptosis, and impaired EPC-induced angiogenesis. EPC-induced angiogenesis was dependent on the presence of nitric oxide, and CRP treatment caused a decrease in endothelial nitric oxide synthase mRNA expression by EPCs. However, all of these detrimental CRP-mediated effects on EPCs were attenuated by pretreatment with rosiglitazone, a peroxisome proliferator-activated receptor-␥ (PPAR␥) agonist. Conclusions-Human recombinant CRP, at concentrations known to predict adverse vascular outcomes, directly inhibits EPC differentiation, survival, and function, key components of angiogenesis and the response to chronic ischemia. This occurs in part via an effect of CRP to reduce EPC eNOS expression. The PPAR␥ agonist rosiglitazone inhibits the negative effects of CRP on EPC biology. The ability of CRP to inhibit EPC differentiation and survival may represent an important mechanism that further links inflammation to cardiovascular disease.

Noninvasive UTMD successfully delivered VEGF and SCF genes into the infarcted heart, increased vascular density, and improved myocardial perfusion and ventricular function. The UTMD technique may be an ideal method for noninvasive, repeated gene delivery after an MI.

Targeted ultrasound delivery of SCF and SDF-1α genes to the infarcted myocardium recruited progenitor cells and increased vascular density. Multiple UTMD treatments enhanced tissue repair, perfusion, and cardiac function. Repeated UTMD therapy may be applied to tailor the number of interventions required to optimize cardiac regeneration after an infarction.

Cardiovascular disease is the principal cause of death in end-stage renal disease (ESRD) patients. Endothelial progenitor cells (EPCs) play a critical role in vascular repair, and improving EPC biology represents a novel therapeutic target. Three groups of age-and gender-matched patients were studied: 1) 10 healthy control, 2) 12 conventional hemodialysis (CHD) patients, and 3) 10 nocturnal hemodialysis (NHD) patients. EPC number and migratory function were assessed. Left ventricular mass index (LVMI) was derived, and correlations between EPC biology, uremic clearance, and LVMI were made. Compared with controls, EPC number and function were markedly impaired in CHD patients [(3.48 Ϯ 1.2 vs. 0.86 Ϯ 0.20%/50,000 cells, P Ͻ 0.05) and (18.8 Ϯ 2.64 vs. 3.75 Ϯ 0.34 cells/high-power field, P Ͻ 0.05), respectively]. In contrast, EPC number and function were normal in NHD patients [(3.48 Ϯ 1.17 vs. 3.83 Ϯ 0.77%/50,000 cells) and (18.8 Ϯ 2.6 vs. 22.2 Ϯ 2.4 cells/high-power field), respectively]. Among ESRD patients, EPC number and function inversely correlated with predialysis urea concentration (r ϭ Ϫ0.40; r ϭ Ϫ0.57), LVMI (r ϭ Ϫ0.41; Ϫ0.46) and systolic BP (r ϭ Ϫ0.58; r ϭ Ϫ0.44). We demonstrate that NHD is associated with restoration of abnormal EPC biology in ESRD. Given the increasing importance of EPCs in the repair and restoration of cardiovascular function, these data have important clinical implications for vascular risk in ESRD patients.

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