Department of Anesthesiology, Johns Hopkins University, Baltimore, MD 21205, USA.
Am J Physiol Heart Circ Physiol. 2013 Aug 1;305(3):H321-9. doi: 10.1152/ajpheart.00099.2013. Epub 2013 May 24.
Experiments investigated maturation of endothelial function in the postnatal period. Carotid arteries isolated from newborn (postnatal day 1, P1) to P21 mice were assessed in myographs at transmural pressure (PTM) of 20 mmHg (P1 blood pressure, BP). Acetylcholine was ineffective in P1 but powerfully dilated P7 arteries, whereas NO-donor DEA-NONOate caused similar dilation at P1 and P7. Dilation to acetylcholine at P7 was abolished by inhibition of NO synthase (NOS) (l-NAME) or of phosphoinositide-3-kinase (PI3K) (wortmannin, LY294002). Endothelial NOS (eNOS) expression decreased in P7 compared with P1 arteries, although acetylcholine increased PO4-eNOS-Ser(1177) in P7 but not in P1 arteries. Endothelial maturation may therefore reflect increased signaling through PI3K, Akt, and eNOS. Systemic BP increases dramatically in the early postnatal period. After exposing P1 arteries to transient increased PTM (50 mmHg, 60 min), acetylcholine caused powerful dilation and increased PO4-eNOS-Ser(1177). Pressure-induced rescue of acetylcholine dilation was abolished by PI3K or NOS inhibition. Transient increased PTM did not affect dilation at P7, or dilation to NO-donor in P1 arteries. Width of endothelial adherens junctions (VE-cadherin immunofluorescence) increased significantly from P1 to P7, and in P1 arteries exposed to transient increased PTM. A function-blocking antibody to VE-cadherin reduced the pressure-induced rescue of acetylcholine responses at P1, and the dilation to acetylcholine in P7 arteries. Therefore, maturation of newborn endothelium dilator function may be induced by increasing BP in the postnatal period. Furthermore, this may be mediated by VE-cadherin signaling at adherens junctions. Interruption of this maturation pathway may contribute to developmental and adult vascular diseases.
实验研究了新生儿期内皮功能的成熟过程。将从新生（出生后第 1 天，P1）至 P21 小鼠分离出的颈总动脉在跨壁压（PTM）为 20mmHg（P1 血压，BP）的情况下在肌动描记器中进行评估。乙酰胆碱在 P1 时无效，但可强力扩张 P7 动脉，而一氧化氮供体 DEA-NONOate 在 P1 和 P7 时引起相似的扩张。在 P7 时，乙酰胆碱的扩张作用被一氧化氮合酶（NOS）抑制剂（l-NAME）或磷酸肌醇 3-激酶（PI3K）抑制剂（wortmannin，LY294002）抑制。与 P1 动脉相比，P7 动脉内皮型一氧化氮合酶（eNOS）表达减少，但乙酰胆碱增加了 P7 而不是 P1 动脉中 PO4-eNOS-Ser（1177）的表达。因此，内皮成熟可能反映了 PI3K、Akt 和 eNOS 信号通路的增强。全身血压在新生儿期急剧增加。在将 P1 动脉暴露于短暂的 PTM 增加（50mmHg，60min）后，乙酰胆碱引起强烈的扩张并增加了 PO4-eNOS-Ser（1177）的表达。PI3K 或 NOS 抑制可消除压力诱导的乙酰胆碱扩张的挽救作用。短暂增加 PTM 不会影响 P7 时的扩张或 P1 动脉中对 NO 供体的扩张。内皮细胞黏附连接（VE-钙黏蛋白免疫荧光）的宽度从 P1 至 P7 显著增加，并且在 P1 动脉中暴露于短暂增加的 PTM 后增加。VE-钙黏蛋白功能阻断抗体可降低 P1 时压力诱导的乙酰胆碱反应的挽救作用，以及 P7 动脉中乙酰胆碱的扩张作用。因此，新生儿期内皮舒张功能的成熟可能是由新生儿期血压升高引起的。此外，这可能是通过黏附连接处的 VE-钙黏蛋白信号转导介导的。该成熟途径的中断可能导致发育和成人血管疾病。
