Long Lasting Microvascular Tone Alteration in Rat Offspring Exposed In Utero to Maternal Hyperglycaemia

Epidemiologic studies have demonstrated that cardiovascular risk is not only determined by conventional risk factors in adulthood, but also by early life events which may reprogram vascular function. To evaluate the effect of maternal diabetes on fetal programming of vascular tone in offspring and its evolution during adulthood, we investigated vascular reactivity of third order mesenteric arteries from diabetic mother offspring (DMO) and control mother offspring (CMO) aged 3 and 18 months. In arteries isolated from DMO the relaxation induced by prostacyclin analogues was reduced in both 3- and 18-month old animals although endothelium (acetylcholine)-mediated relaxation was reduced in 18-month old DMO only. Endothelium-independent (sodium nitroprusside) relaxation was not affected. Pressure-induced myogenic tone, which controls local blood flow, was reduced in 18-month old CMO compared to 3-month old CMO. Interestingly, myogenic tone was maintained at a high level in 18-month old DMO even though agonist-induced vasoconstriction was not altered. These perturbations, in 18-months old DMO rats, were associated with an increased pMLC/MLC, pPKA/PKA ratio and an activated RhoA protein. Thus, we highlighted perturbations in the reactivity of resistance mesenteric arteries in DMO, at as early as 3 months of age, followed by the maintenance of high myogenic tone in older rats. These modifications are in favour of excessive vasoconstrictor tone. These results evidenced a fetal programming of vascular functions of resistance arteries in adult rats exposed in utero to maternal diabetes, which could explain a re-setting of vascular functions and, at least in part, the occurrence of hypertension later in life.

流行病学研究表明，心血管疾病风险不仅由成年时期的传统危险因素决定，还可受早期生命事件影响——此类事件可对血管功能产生程序化重塑。为探究母体糖尿病对子代血管张力胎儿程序化编程的影响及其在成年后的演变规律，本研究对3月龄与18月龄的母体糖尿病子代（diabetic mother offspring, DMO）及对照母体子代（control mother offspring, CMO）的三级肠系膜动脉（third order mesenteric arteries）血管反应性进行了检测。从DMO组分离的动脉样本中，前列环素类似物诱导的血管舒张反应在3月龄和18月龄动物中均有所减弱；而内皮依赖性（乙酰胆碱介导）的血管舒张反应仅在18月龄DMO组中出现降低。非内皮依赖性（硝普钠介导）的血管舒张反应则未受影响。调控局部血流的压力诱导肌源性张力，在18月龄CMO组中较3月龄CMO组有所下降。值得注意的是，尽管激动剂诱导的血管收缩反应未发生改变，但18月龄DMO组的肌源性张力仍维持在较高水平。18月龄DMO大鼠的上述血管功能异常，与pMLC/MLC、pPKA/PKA比值升高以及RhoA蛋白激活密切相关。综上，本研究揭示：早在3月龄时，DMO组阻力型肠系膜动脉的反应性即出现异常；而在老龄大鼠中，其肌源性张力持续维持于较高水平。此类改变倾向于引发过度的血管收缩张力。本研究结果证实，宫内暴露于母体糖尿病的成年大鼠，其阻力动脉的血管功能已出现胎儿程序化编程改变，这或可解释血管功能的重置现象，并至少部分参与成年后高血压的发生。