CGMP-MEDIATED VASODILATION IN PERINATAL LUNG

描述：在血管平滑肌细胞中，内皮源性NO、ANF、 硝基血管扩张剂和外源性NO通过激活 随着细胞内cGMP浓度的增加，PKG级联反应。这个 NO-cGMP-PKG通路在低血管形成中的关键作用 肺循环中的阻力。申请人和其他人已经被 研究这一途径，到目前为止主要集中在酶的研究上 (鸟苷酸环化酶和磷酸二酯酶)调节cGMP水平。研究 AR现在建议确定cGMP升高的机制 血管平滑肌细胞最终导致血管扩张。 肺在出生时就开始发育了。目标1将确定PKG的作用 在cGMP介导的血管扩张和发育之间的联系 围产期cGMP诱导的血管扩张和PKG活性增加 将会被探索。蛋白激酶G 1-α和1-β的具体作用 亚型将被确定。目标2将确定蛋白质的作用 PKG介导的血管扩张中的磷酸酶，PP1，PP2A和PP2B。目标3将 测定氧分压对心肌细胞PKG和磷酸酶活性的影响 围产期。所有研究都将在绵羊物种中进行，并且 分离的血管张力实验将与分子和 实验方案中的生化研究。调查人员已经 表明肺动脉的反应可能与那些 因此，将在动脉和静脉中进行实验。 出生时肺血管阻力正常下降的任何障碍 结果导致新生儿肺动脉高压和显著发病率 和死亡率。从这些研究中获得的知识可能会带来更好的 对出生时肺血管扩张机制的了解 制定策略预防和治疗老年人的肺动脉高压 围产期。

DESCRIPTION: In vascular smooth muscle cells, endothelium-derived NO, ANF, nitrovasodilators and exogenous NO-induced vasodilation by activation of the PKG cascade following increases in intracellular cGMP concentrations. The NO-cGMP-PKG pathway plays a pivotal role in establishing low vascular resistance in the pulmonary circulation. The applicant and others have been studying this pathway and thus far has focused on studies of the enzymes (guanylyl cyclase and phosphodiesterase) that regulate cGMP levels. Studies ar now proposed to determine the mechanisms by which elevated cGMP in vascular smooth muscle cells ultimately result in vasodilation in the developing lung a the time of birth. Aim 1 will determine the role of PKG in cGMP-mediated vasodilation and the link between the developmental increase in cGMP-induced dilation in the perinatal period and PKG activity will be explored. The specific roles of PKG type 1-alpha and 1-beta isoforms will be determined. Aim 2 will determine the role of the protein phosphatases, PP1 PP2A, and PP2B, in PKG-mediated vasodilation. Aim 3 will determine the effect of oxygen tension o PKG and phosphatase activity in the perinatal period. All studies will be conducted in the ovine species, and isolated vessel tension experiments will b complemented with molecular and biochemical studies in the experimental protocols. The investigators have shown that responses of pulmonary arteries may be quite different from those of veins, and experiments will therefore be done in both arteries and veins. Any disturbance in the normal fall in pulmonary vascular resistance at birth results in pulmonary hypertension of th newborn and significant morbidity and mortality. Knowledge derived from these studies could lead to a better understanding of the mechanisms of pulmonary vasodilation at birth and thus to develop strategies to prevent and treat pulmonary hypertension in the perinatal period.