Vinci Maria Cristina, Bellik Lydia, Filippi Sandra, Ledda Fabrizio, Parenti Astrid
Laboratory of Vascular Pharmacology, Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2140-7. doi: 10.1152/ajpheart.00390.2007. Epub 2007 Jul 27.
Catecholamines have been shown to be involved in vascular remodeling through the stimulation of alpha(1)-adrenoceptors (alpha(1)-ARs). Recently, it has been demonstrated that catecholamines can stimulate angiogenesis in pathological conditions, even if the mechanisms and the AR subtypes involved still remain unclear. We investigated the influence of hypoxia (3% O(2)) on the ability of picomolar concentrations of phenylephrine (PHE), which are unable to induce any vascular contraction, to induce a trophic effect in human endothelial cells through stimulation of the alpha(1D)-subtype ARs. PHE, at picomolar concentrations, significantly promoted pseudocapillary formation from fragments of human mature vessels in vitro. Exposure to hypoxia significantly potentiated this effect, which was inhibited by the selective alpha(1D)-AR antagonist BMY-7378 and by the nitric oxide synthase inhibitor L-NAME, suggesting that alpha(1D)-ARs were involved in this effect through activation of the nitric oxide pathway. Proliferation and migration of HUVEC were also affected by picomolar PHE concentrations. Again, these effects were significantly potentiated in cells exposed to hypoxia and were inhibited by BMY-7378 and by N(G)-nitro-L-arginine methyl ester. Conversely, the alpha(1A)-AR-selective antagonist (S)-(+)-niguldipine hydrochloride and the alpha(1B)-AR antagonist chloroethylclonidine dihydrochloride did not modify endothelial cell migration and proliferation in response to PHE. These results demonstrate that the stimulation of alpha(1D)-ARs, triggered by picomolar PHE concentrations devoid of any contractile vascular effects, induces a proangiogenic phenotype in human endothelial cells that is enhanced in a hypoxic environment. The role of alpha(1D)-ARs may become more prominent in the adaptive responses to hypoxic vasculature injury.
儿茶酚胺已被证明可通过刺激α1-肾上腺素能受体（α1-ARs）参与血管重塑。最近，已证实儿茶酚胺在病理条件下可刺激血管生成，尽管其涉及的机制和AR亚型仍不清楚。我们研究了缺氧（3% O2）对皮摩尔浓度的去氧肾上腺素（PHE）诱导人内皮细胞产生营养作用能力的影响，该浓度的PHE无法诱导任何血管收缩，其通过刺激α1D-亚型ARs发挥作用。皮摩尔浓度的PHE在体外显著促进了人成熟血管片段形成假毛细血管。暴露于缺氧环境显著增强了这种作用，该作用被选择性α1D-AR拮抗剂BMY-7378和一氧化氮合酶抑制剂L-NAME抑制，这表明α1D-ARs通过激活一氧化氮途径参与了此作用。皮摩尔浓度的PHE也影响了人脐静脉内皮细胞（HUVEC）的增殖和迁移。同样，这些作用在暴露于缺氧环境的细胞中显著增强，并被BMY-7378和N-硝基-L-精氨酸甲酯抑制。相反，α1A-AR选择性拮抗剂（S）-（+）-盐酸尼鲁地平以及α1B-AR拮抗剂盐酸氯乙可乐定并未改变内皮细胞对PHE的迁移和增殖反应。这些结果表明，皮摩尔浓度的PHE引发的α-1D-ARs刺激，在无任何血管收缩作用的情况下，可诱导人内皮细胞产生促血管生成表型，且在缺氧环境中增强。α1D-ARs的作用在对缺氧性血管损伤的适应性反应中可能变得更加突出。
