No abstract

The use of pro-angiogenic growth factors in ischemia models has been associated with limited success in the clinical setting, in part owing to the short lived effect of the injected cytokine. The use of a microparticle system could allow localized and sustained cytokine release and consequently a prolonged biological effect with induction of tissue revascularization. To assess the potential of VEGF(165) administered as continuous release in ischemic disease, we compared the effect of delivery of poly(lactic-co-glycolic acid) (PLGA) microparticles (MP) loaded with VEGF(165) with free-VEGF or control empty microparticles in a rat model of ischemia-reperfusion. VEGF(165) loaded microparticles could be detected in the myocardium of the infarcted animals for more than a month after transplant and provided sustained delivery of active protein in vitro and in vivo. One month after treatment, an increase in angiogenesis (small caliber caveolin-1 positive vessels) and arteriogenesis (α-SMA-positive vessels) was observed in animals treated with VEGF microparticles (p<0.05), but not in the empty microparticles or free-VEGF groups. Correlating with this data, a positive remodeling of the heart was also detected in the VEGF-microparticle group with a significantly greater LV wall thickness (p<0.01). In conclusion, PLGA microparticle is a feasible and promising cytokine delivery system for treatment of myocardial ischemia. This strategy could be scaled up and explored in pre-clinical and clinical studies.

Pravastatin improved the vascular reactivity in this murine model of preeclampsia by decreasing sFlt-1 levels. Statins should be evaluated for the prevention of the vascular abnormalities of preeclampsia.

Partial renal ablation leads to progressive renal insufficiency and is a model of chronic renal failure from diverse causes. We find that mice develop functional and morphologic characteristics of chronic renal failure after partial renal ablation, including glomerular sclerosis, systemic hypertension, and reduced glomerular filtration. However, we now report that littermates with a homozygous deletion of the gene for the cyclin-dependent kinase inhibitor, p21 WAF1͞CIP1 , do not develop chronic renal failure after ablation. The markedly different reactions of the p21(؉͞؉) and p21(؊͞؊) animals was not because of differences in glomerular number or degree of renal growth but rather because of the presence or absence of a normal p21 gene. Although the reaction to the stress of renal ablation is both hyperplastic and hypertrophic in the presence of a functional p21 gene, it would appear that the absence of the p21 gene may induce a more hyperplastic reaction because proliferating-cell nuclear antigen expression, a marker of cell-cycle progression, in the renal epithelium of the remnant kidney was more than five times greater in the p21(؊͞؊) mice than in the p21(؉͞؉) animals. Because p21 is a potent inhibitor of the cell cycle, we speculate that p21 regulates the balance between hyperplasia and hypertrophy after renal ablation. We propose that this change in response inhibits the development of chronic renal failure. These studies suggest that controlling p21 function may ameliorate or even prevent progressive endstage renal disease.The removal of substantial amounts of renal tissue is followed by a progressive decline in renal function (1, 2). Glomerular hypertrophy occurs early in response to this ablation and is accompanied by short-term increases in glomerular filtration (3, 4). These structural and functional adaptations to loss of excretory function are thought to be maladaptive and to influence the progression to end-stage renal disease. Progression is initially seen as localized increases in mesangial matrix that then leads to global glomerular sclerosis and is usually associated with systemic hypertension, which has been speculated to accelerate its course. Although the early glomerular hypertrophy and hyperfunction, especially the glomerular hypertension that determines it, have been invoked as predeterminants of the later destructive effects of renal ablation, there is no established causal link between these events and the progressive nature of the renal disease.Acute short-term stress in the kidney provokes molecular responses that involve the expression of several genes, including the cyclin-dependent kinase inhibitor p21 (5). p21 plays a critical role in processes by which nuclear events subsequent to environmental stress are regulated. It is induced to very high levels by oxidative stress (6) and DNA damage (7). The p21 protein (8) acts as an inhibitor of cyclin-dependent kinase activity (9) and effectively stops cell-cycle progression (8, 9). It is overexpressed in many cells undergoing senes...