Abstract-Inhibitors of angiogenic factors are known to be upregulated, and their levels increase in the maternal circulation before the onset of preeclampsia. We reproduced a previously characterized model of preeclampsia by adenoviral overexpression of the soluble vascular endothelial growth factor (VEGF) receptor sFlt-1 (also referred to as sVEGFR-1) in pregnant and nonpregnant Sprague-Dawley rats. Animals were treated with VEGF121 at 0, 100, 200, or 400 g/kg once or twice daily (nϭ8 per group; 64 total) and compared with normal control animals (nϭ4 per group) by examination of systolic blood pressure, urinary albumin and creatinine, renal histopathology, and glomerular gene expression profiling. sFlt-1 expression induced hypertension with proteinuria and glomerular endotheliosis and significant changes in gene expression. VEGF121 treatment alleviated these symptoms and reversed 125 of 268 sFlt-1-induced changes in gene expression. VEGF121 had beneficial effects in this rat model of preeclampsia without apparent harm to the fetus. Further study of VEGF121 as a potential therapeutic agent for preeclampsia is warranted.

The transition from compensated hypertrophy to failure in spontaneously hypertensive rats (SHR) of advanced age is associated with a marked increase in collagen, a reduction in myocyte mass, and a reduction in maximum Ca(2+)-activated myofibrillar force. We hypothesized that the reduction in myocyte mass and associated functional loss may be due to increased cell death by apoptosis. To test this hypothesis, we studied hearts from failing (SHR-F) and nonfailing SHR (SHR-NF) and age-matched Wistar-Kyoto rats (WKY). In addition, hearts from SHR-F that had been treated with an angiotensin-converting enzyme inhibitor (captopril) for an average of 27 days were also studied. Apoptotic cells were quantified in cross sections of myocardium by the terminal deoxynucleotidyltransferase- mediated 2'-deoxyuridine 5'-triphosphate nick end labeling technique. To identify the type of the cells undergoing apoptosis, sections were also stained for alpha-sarcomeric actin. Apoptotic cells were significantly increased in the SHR-F (38.92 +/- 12.79 vs. 8.05 +/- 3.98 cells/100,000 nuclei in SHR-NF; P < 0.05 and vs. 2.21 +/- 1.4 cells/100,000 nuclei in WKY; P < 0.01). Captopril treatment of SHR-F reduced the number of apoptotic cells to the level in SHR-NF (9.17 +/- 1.53 cells/100,000 nuclei; P < 0.01 vs. SHR-F). Most apoptotic cells were of cardiac myocyte origin. There was no significant difference in Bcl-2 protein expressed by hearts among the three groups. WAF-1 mRNA levels were increased in both SHR groups vs. WKY; in SHR-F, the density of WAF-1 mRNA was higher than in SHR-NF. Thus increased numbers of apoptotic cells are present in failing SHR hearts, suggesting that apoptosis might be a mechanism involved in the reduction of myocyte mass that accompanies the transition from stable compensation to heart failure in this model. Administration of the angiotensin-converting enzyme inhibitor captopril, which ameliorates heart failure in this model, is associated with a reduction in the exaggerated apoptosis that accompanies heart failure.

Abstract-To characterize remodeling of elastic arteries with aging and to investigate its potential mechanisms, matrix metalloproteinase-2 (MMP-2), intracellular adhesive molecule-1 (ICAM-1), transforming growth factor-␤ (TGF-␤), and fibronectin protein levels were measured in the aortas of young adult (6 months) and aged (30 months) Fischer 344XBN rats. At 30 versus 6 months, the thickness of the intima was 5-fold greater and contained marked increases in TGF-␤ and ICAM-1, and fibronectin expression was enhanced throughout the aortic wall. Total MMP-2 protein (Western blot) of 30-month-old rats was increased 8-fold over that of 6-month-old rats (0.166Ϯ0.032 versus 0.020Ϯ0.006; PϽ0.01), and staining and activity were regionally localized to the intima, often near breaks in the internal elastic membrane and lamellae. Early passage, explanted smooth muscle cells (SMC) from aged aorta secreted more MMP-2 than those from young aorta; while basal MMP-2 production did not differ with age, after stimulation with cytokines (interleukin-1, tumor necrosis factor-␣, or TGF-␤, 10 ng/mL each for 24 hours), MMP-2 production in SMC from 30-month-old rats increased to levels greater than those in 6-month-old rats. Thus, enhanced expression of TGF-␤, MMP-2, and ICAM-1 in the thickened vascular intima of aged rats may in part be produced by exaggerated SMC responses to cytokines and may have potential roles in intimal remodeling with aging. (Hypertension. 1999;33:116-123.)