Lamireau Delphine, Nuyt Anne Monique, Hou Xin, Bernier Sylvie, Beauchamp Martin, Gobeil Fernand, Lahaie Isabelle, Varma Daya R, Chemtob Sylvain
Research Center, Hôpital Sainte-Justine, Department of Pediatrics and Pharmacology, Université de Montréal, Montreal, Canada.
Stroke. 2002 Dec;33(12):2992-8. doi: 10.1161/01.str.0000039340.62995.f2.
Reduced endothelium-dependent vasorelaxation partly due to loss of nitric oxide (NO) bioavailability occurs in most cases of chronic hypertension. Intrauterine nutritional deprivation has been associated with increased risk for hypertension and stroke, associated with relaxant dysfunction and decreased vascular compliance, but the underlying mechanisms are not known. The present studies were undertaken to investigate whether endothelial dysfunction associated with altered NO-dependent vasodilatation pathways is also observed in a model of in utero programming of hypertension.
Pregnant Wistar rats were fed a normal (18%), low (9%), or very low (6%) protein isocaloric diet during gestation. Vasomotor response of resistance cerebral microvessels (<50 micro m) was studied in adult offspring of dams fed the 18% and 9% protein diets by a video imaging technique. Endothelial NOS (eNOS), soluble guanylate cyclase (sGC), and K(Ca) channel expression were measured by Western blot. NO synthase (NOS) activity was measured enzymatically as well as in situ by NADPH diaphorase staining.
Litter size and survival to adulthood were not affected by the diets. Birth weights of offspring of dams fed the 6% diet were markedly lower than those of dams fed the 9% diet, which were marginally lower than those of controls. Systolic blood pressures of adult offspring of mothers in the 6% and 9% groups were comparably greater (156+/-2 and 155+/-1 mm Hg, respectively) than that of control offspring (137+/-1 mm Hg); we therefore focused on the 9% and 18% groups. Cerebral microvessel constriction to thromboxane A(2) mimetic and dilation to carba-prostaglandin I(2) did not differ between diet groups. In contrast, vasorelaxation to the NO-dependent agents substance P and acetylcholine was diminished by 50% in low protein-exposed offspring, but eNOS expression and activity were similar between the 2 diet groups. Vasorelaxant response to the NO donor sodium nitroprusside was also decreased and was associated with reduced (by 50% to 65%) cGMP levels and sGC expression. cGMP analogues caused comparable vasorelaxation in the 2 groups. Expression of K(Ca) (another important mediator of NO action) and relaxation to the K(Ca) opener NS1619 were unchanged by antenatal diet.
Maternal protein deprivation, which leads to hypertension in the offspring, is associated with diminished NO-dependent relaxation of major organ (cerebral) microvasculature, which seems to be largely attributed to decreased sGC expression and cGMP levels. The study provides an additional explanation for abnormal vasorelaxation in nutrient-deprived subjects in utero.
在大多数慢性高血压病例中，内皮依赖性血管舒张功能降低，部分原因是一氧化氮（NO）生物利用度丧失。子宫内营养剥夺与高血压和中风风险增加有关，伴有舒张功能障碍和血管顺应性降低，但其潜在机制尚不清楚。本研究旨在探讨在高血压子宫内编程模型中是否也观察到与NO依赖性血管舒张途径改变相关的内皮功能障碍。
妊娠期间，给怀孕的Wistar大鼠喂食正常（18%）、低（9%）或极低（6%）蛋白质等热量饮食。通过视频成像技术研究喂食18%和9%蛋白质饮食的母鼠成年后代中阻力脑微血管（<50μm）的血管运动反应。通过蛋白质印迹法测量内皮型一氧化氮合酶（eNOS）、可溶性鸟苷酸环化酶（sGC）和钾钙通道（K(Ca)）的表达。通过酶法以及NADPH黄递酶染色原位测量一氧化氮合酶（NOS）活性。
窝仔数和成年存活率不受饮食影响。喂食6%饮食的母鼠后代出生体重明显低于喂食9%饮食的母鼠后代，后者略低于对照组。6%和9%组母亲的成年后代收缩压（分别为156±2和155±1 mmHg）显著高于对照组后代（137±1 mmHg）；因此，我们重点关注9%和18%组。饮食组之间，大脑微血管对血栓素A2类似物的收缩反应和对卡巴前列环素I2的舒张反应没有差异。相比之下，低蛋白暴露后代对NO依赖性介质P物质和乙酰胆碱的血管舒张反应降低了50%，但两组之间eNOS的表达和活性相似。对NO供体硝普钠的血管舒张反应也降低，且与cGMP水平和sGC表达降低（50%至65%）相关。cGMP类似物在两组中引起类似的血管舒张。产前饮食对K(Ca)（NO作用的另一个重要介质）的表达以及对K(Ca)开放剂NS1619的舒张反应没有影响。
母体蛋白质剥夺导致后代高血压，与主要器官（脑）微血管的NO依赖性舒张功能减弱有关，这似乎主要归因于sGC表达和cGMP水平降低。该研究为子宫内营养剥夺个体的异常血管舒张提供了额外的解释。
