Institutes of Physiology I and Molecular Psychiatry, Life and Brain Center, University of Bonn, 53127 Bonn, Germany.
Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18710-5. doi: 10.1073/pnas.1308130110. Epub 2013 Oct 28.
Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites. This is underscored by the prominent vasoconstrictive effect of AEA on pulmonary arteries and strongly reduced HPV in FAAH(-/-) mice and wild-type mice upon pharmacological treatment with FAAH inhibitor URB597. In addition, mass spectrometry measurements revealed a clear increase of AEA and the FAAH-dependent metabolite arachidonic acid in hypoxic lungs of wild-type mice. We have identified pulmonary vascular smooth muscle cells as the source responsible for hypoxia-induced AEA generation. Moreover, either FAAH(-/-) mice or wild-type mice treated with FAAH inhibitor URB597 are protected against hypoxia-induced pulmonary hypertension and the concomitant vascular remodeling in the lung. Thus, the AEA/FAAH pathway is an important mediator of HPV and is involved in the generation of pulmonary hypertension.
内源性大麻素是器官内稳态的重要调节剂。虽然它们在系统性血管中的作用已经得到了广泛的研究，但它们对肺血管的影响仍不明确。本文表明，内源性大麻素花生四烯酸乙醇胺（AEA）是缺氧性肺血管收缩（HPV）的关键介质，通过脂肪酸酰胺水解酶（FAAH）依赖性代谢物起作用。这一点在 AEA 对肺动脉的显著血管收缩作用以及 FAAH(-/-) 小鼠和给予 FAAH 抑制剂 URB597 治疗的野生型小鼠中 HPV 明显减弱得到了强调。此外，质谱测量显示，在野生型小鼠的低氧肺中，AEA 和 FAAH 依赖性代谢物花生四烯酸的含量明显增加。我们已经确定肺血管平滑肌细胞是负责缺氧诱导 AEA 生成的来源。此外，FAAH(-/-) 小鼠或给予 FAAH 抑制剂 URB597 治疗的野生型小鼠可预防缺氧引起的肺动脉高压和肺中伴随的血管重塑。因此，AEA/FAAH 途径是 HPV 的重要介质，参与肺动脉高压的发生。
