脑动脉内皮源性前列腺素F2α对血管舒缩功能的调控及在高胆固醇血症状态下的作用和分子机制

Prostacyclin (PGI2) is the main product of cyclooxygenase (COX) in vascular endothelium and plays an important role in regulating vasomotor tone. Our preliminary data showed that besides PGI2, prostaglandin F2α (PGF2α) was produced in large amounts by rabbit cerebral arteries. The later is known to be a strong vasoconstrictor. This novel finding together with evidence in the literature prompted us to hypothesize that because of lower expression of PGI2 synthase (PGIS) and/or higher expression of PGFS, PGF2α is abundantly produced by COX metabolic pathway in the endothelium of cerebral arteries besides PGI2, and that PGI2 induces vasodilation, which is compromised by the vasoconstrictive effect of PGF2α (via acting on FP receptors). The COX pathway can contribute to endothelial dysfunction. Therefore, we further proposed that in pathological conditions such as hypercholesterolemia, COX-2 is upregulated and PGIS is selectively nitrated in cerebral arteries, resulting in the increase of PGF2α production which add to endothelial dysfunction. Therefore, this project will use physiological, pathophysiological and biochemical methods to substantiate our above hypotheses. We aim to determine the production and vasomotor effect of PGF2α and the related molecular mechanisms in health and disease, and our results are expected to provide novel insights into the regulation of cerebral vascular function as well as the pathology and pathophysiology of hypercholesterolemia-related cerebral vascular diseases, which could provide new targeting information for the prevention or treatment of these diseases.

内皮COX主要产生PGI2调节血管功能。我们前期实验表明，兔脑动脉除产生PGI2外还大量产生PGF2α，后者具强烈血管收缩作用。根据我们最新实验结果及文献报道，申请人首次提出：由于PGI2合成酶（PGIS）的低表达和/或PGFS高表达，脑动脉COX代谢同时产生PGI2和PGF2α，后者可对抗部分PGI2引起的血管舒张效应。 且COX代谢在内皮功能异常中起着重要作用。因此，我们进一步设想：在高胆固醇血症等病理状态下，脑动脉COX-2的表达上调及PGIS选择性发生硝基化可导致PGF2α产生相对增多，从而加重内皮功能失调的病理生理过程。本项目拟采用生理、病理生理、及生物化学等方法充分论证上述假说，以确定正常及病理状态下脑动脉PGF2α的产生及参与调控血管功能的分子机制。预期研究结果将为脑血管功能调控及相关疾病的病理、病理生理机制提供新的理论和实验依据，并为此类疾病的防治提供新的干预靶点信息。

血管内皮主要通过COX-1产生PGI2而调节血管功能。然而脑动脉COX代谢的主要产物与其下游通路、以及在高胆固醇血症等病理状态下的变化等尚不清楚。本项目利用液质联用（HPLC-MS）及血管张力检测等方法研究了脑动脉内皮COX代谢通路及其对脑动脉舒缩功能的调控及分子机制，并在此基础上进一步研究了在高胆固醇血症状态下，血管前列腺素类的产生及对血管舒缩功能调控作用的变化及机制。结果显示，与颈动脉相比，脑动脉与外周颈动脉PGF2α的合成酶AKR1C3与AKR1B1的表达相同，但PGI2合成酶PGIS表达较低，脑动脉除产生PGI2外还产生大量的PGF2α。脑动脉TP受体低表达且FP受体高表达，故而PGF2α作用于FP受体而诱导血管收缩，从而对抗同时产生的PGI2所引起的舒张作用，共同参与血管舒缩功能调控。在高脂高胆固醇状态下，整体血管的COX通路并未发生改变，但斑块部位的COX-2上调，与COX-1一起参与血管功能调控。研究结果为脑血管功能调控及相关疾病的病理、病理生理机制提供新的理论和实验依据，并为此类疾病的防治提供新的干预靶点信息。