Joey P. Granger

Recombinant Vascular Endothelial Growth Factor 121 Infusion Lowers Blood Pressure and Improves Renal Function in Rats With PlacentalIschemia-Induced Hypertension

Antagonism of vascular endothelial growth factor (VEGF) signaling by soluble fms-like tyrosine kinase 1 occurs during preeclampsia and is proposed to play an important role in the pathogenesis of preeclampsia. We reported recently that hypertension associated with chronic reductions in uteroplacental perfusion pressure (RUPP) is associated with increased soluble fms-like tyrosine kinase 1 and decreased free VEGF. Whether restoration of circulating VEGF can restore renal function and chronically decrease arterial pressure associated with placental ischemia remains unknown. We hypothesized that chronic infusion of VEGF121 would attenuate hypertension, increase glomerular filtration rate, and reverse the endothelial dysfunction associated with chronic RUPP. VEGF121 (at either 90 or 180 &mgr;g/kg per day) was administered for 5 days via osmotic minipump placed IP. Mean arterial pressure, renal function, and tissues were obtained on day 19 of pregnancy from RUPP+VEGF, RUPP, and normal pregnant dams. Mean arterial pressure was increased in the RUPP (131±3 mm Hg) compared with the normal pregnant (102±1 mm Hg) rats, and infusion of VEGF121 resolved the hypertension (105±5 mm Hg). Glomerular filtration rate was decreased in the RUPP dams (1.5±0.3 mL/min) and restored to normal pregnant levels (3.1±0.5 mL/min) by VEGF121 treatment (3.1±0.4 mL/min). Effective renal plasma flow, decreased by RUPP, was also increased by VEGF121 infusion. Relaxation to acetylcholine was enhanced by the VEGF treatment (P<0.05). These data demonstrate that chronic infusion of VEGF121 during late gestation restores glomerular filtration rate and endothelial function and reduces high blood pressure associated with placental ischemia. The present results suggest that VEGF121 may be a candidate molecule for management of preeclampsia and its related complications.

Mechanism of the blood pressure and renal hemodynamic effects of captopril

THis study was designed to investigate the mechanisms of captoprils chronic effect on arterial pressure and renal function. In dogs maintained on high sodium intake (250 mEq/day), 6 days of captopril infusion caused no change in arterial pressure, renal hemodynamics, sodium excretion or plasma aldosterone concentration. Infusion of captopril for 7 days also caused no significant changes in arterial pressure or renal function in dogs made hypertensive by chronic infusion of angiotensin II and high sodium intake, a model of hypertension in which plasma renin activity is undetectable and prostaglandin and bradykinin formation may be elevated. In dogs maintained on low sodium intake, chronic infusion of captopril decreased arterial pressure and plasma aldosterone concentration markedly while increasing effective renal plasma flow. Infusion of aldosterone (200 micrograms/day) for 8 days during captopril infusion restored plasma aldosterone concentration but did not significantly change arterial pressure or renal function, indicating that decreased plasma aldosterone concentration did not play a major role in the hypertensive and renal effects of captopril. However, angiotensin II infusion (10 ng/kg/min) for 8 days during captopril infusion restored arterial pressure, plasma aldosterone concentration and renal function toward control levels. These data suggest that the effects of captopril on arterial pressure, renal hemodynamics and electrolyte excretion are mediated primarily by decreased angiotensin II formation.

ACE2 and ANG-(1-7) in the gravid uterus: the new players on the block

there has been long-standing interest in the widely recognized role of the renin-angiotensin system (RAS) in electrolyte homeostasis and regulation of hemodynamics in both diseased and nondiseased states ([5][1]). While the role of the RAS in the long-term regulation of renal function and arterial

Nitric oxide synthase-mediated blood pressure regulation in obese melanocortin-4 receptor-deficient pregnant rats

Although obesity increases the risk for hypertension in pregnancy, the mechanisms responsible are unknown. Increased nitric oxide (NO) production results in vasodilation and reduced blood pressure during normal pregnancy in lean rats; however, the role of NO is less clear during obese pregnancies. We examined the impact of obesity on NO synthase (NOS)-mediated regulation of blood pressure during pregnancy by testing the hypothesis that NOS activity, expression, and regulation of vascular tone and blood pressure are reduced in obese pregnant rats. At gestational day 19, melanocortin-4 receptor (MC4R)-deficient obese rats (MC4R) had greater body weight and fat mass with elevated blood pressure and circulating sFlt-1 levels compared with MC4R pregnant rats. MC4R pregnant rats also had less circulating cGMP levels and reduced total NOS enzymatic activity and expression in mesenteric arteries. Despite decreased biochemical measures of NO/NOS in MC4R rats, NOS inhibition enhanced vasoconstriction only in mesenteric arteries from MC4R rats, suggesting greater NOS-mediated tone. To examine the role of NOS on blood pressure regulation in obese pregnant rats, MC4R and MC4R pregnant rats were administered the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 100 mg/l) from gestational day 14 to 19 in drinking water. The degree by which l-NAME raised blood pressure was similar between obese and lean pregnant rats. Although MC4R obese pregnant rats had elevated blood pressure associated with reduced total NOS activity and expression, they had enhanced NOS-mediated attenuation of vasoconstriction, with no evidence of alterations in NOS-mediated regulation of blood pressure.

Animal Models for Investigating Pathophysiological Mechanisms of Preeclampsia

The goal of this chapter is to review some of the more widely studied and/or recently developed animal models used to investigate mechanisms that link placental pathology with maternal endothelial activation/dysfunction and vascular abnormalities of preeclampsia. We attempted to highlight the advantages and limitations of these models. While studies in animal models have limitations, utilization of these models allows investigators to directly test whether certain factors found in preeclamptic women can indeed lead to hypertension and other manifestations of preeclampsia. Thus, animal models are useful in advancing our knowledge of preeclampsia and should undoubtedly be of greater use in future studies on mechanisms and the development of specific treatments.