Endothelial mechanisms for inactivation of inflammation-induced hyperpermeability.
Endothelial mechanisms for inactivation of inflammation-induced hyperpermeability.
复制标题
DOI：
10.1152/ajpheart.00543.2022
复制
发表时间：
2023-05-01
影响因子：
4.8
通讯作者：
Duran, Walter N.
中科院分区：
文献类型：
--
作者：
Nepali, Prerna R.;Burboa, Pia C.;Lillo, Mauricio A.;Muica, Patricio E.;Iwahashi, Toru;Zhang, Jihang;Duran, Ricardo G.;Boric, Mauricio;Golenhofen, Nikola;Kim, David D.;Alves, Natascha G.;Thomas, Andrew P.;Breslin, Jerome W.;Sanchez, Fabiola A.;Duran, Walter N.
微血管通透性过高是炎症的标志。高渗透性的许多负面影响是由于其持久性超过了保持器官功能所需的程度。因此，我们提出，针对性的治疗方法，专注于终止高渗透性的机制，将避免长期高渗透性的负面影响，同时保留其短期的有益效果。我们测试了炎症激动剂信号传导导致高通透性并启动cAMP依赖性通路的延迟级联导致高通透性失活的假设。我们应用血小板活化因子（PAF）和血管内皮生长因子（VEGF）诱导高通透性。我们使用Epac 1激动剂选择性地刺激cAMP激活的交换蛋白（Epac 1），并促进高通透性的失活。Epac 1的刺激灭活了小鼠提睾肌和人微血管内皮细胞（HMVEC）中激动剂诱导的通透性过高。PAF在1 min内诱导HMVECs产生一氧化氮（NO）和高通透性，并在15-20 min内诱导NO依赖性cAMP浓度升高。PAF以NO依赖的方式触发血管舒张刺激磷蛋白（VASP）的磷酸化。Epac 1刺激促进了HMVECs和野生型小鼠心肌微血管内皮细胞（MyEnd）中eNOS的胞质-细胞膜转位，但在VASP敲除小鼠的MyEnd细胞中没有。我们证明，PAF和VEGF导致高通透性和刺激cAMP/Epac 1途径，以血管紧张素受体激动剂诱导的内皮/微血管高通透性。失活涉及VASP辅助的eNOS从细胞质到内皮细胞膜的易位。我们证明，高渗透性是一个自限性的过程，其定时失活是微血管内皮细胞的内在特性，维持血管稳态，以应对炎症条件。新&值得注意的是，微血管通透性过高的终止迄今为止被认为是去除所应用的促炎激动剂的被动结果。我们提供的体内和体外证据表明：1）高通透性的失活是一个主动调节的过程，2）促炎激动剂（PAF和VEGF）刺激微血管高通透性并启动终止高通透性的内皮机制，3）eNOS定位-易位在内皮高通透性的激活-失活级联反应中至关重要。
Microvascular hyperpermeability is a hallmark of inflammation. Many negative effects of hyperpermeability are due to its persistence beyond what is required for preserving organ function. Therefore, we propose that targeted therapeutic approaches focusing on mechanisms that terminate hyperpermeability would avoid the negative effects of prolonged hyperpermeability while retaining its short-term beneficial effects. We tested the hypothesis that inflammatory agonist signaling leads to hyperpermeability and initiates a delayed cascade of cAMP-dependent pathways that causes inactivation of hyperpermeability. We applied platelet-activating factor (PAF) and vascular endothelial growth factor (VEGF) to induce hyperpermeability. We used an Epac1 agonist to selectively stimulate exchange protein activated by cAMP (Epac1) and promote inactivation of hyperpermeability. Stimulation of Epac1 inactivated agonist-induced hyperpermeability in the mouse cremaster muscle and in human microvascular endothelial cells (HMVECs). PAF induced nitric oxide (NO) production and hyperpermeability within 1 min and NO-dependent increased cAMP concentration in about 15–20 min in HMVECs. PAF triggered phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in a NO-dependent manner. Epac1 stimulation promoted cytosol-to-membrane eNOS translocation in HMVECs and in myocardial microvascular endothelial (MyEnd) cells from wild-type mice, but not in MyEnd cells from VASP knockout mice. We demonstrate that PAF and VEGF cause hyperpermeability and stimulate the cAMP/Epac1 pathway to inactivate agonist-induced endothelial/microvascular hyperpermeability. Inactivation involves VASP-assisted translocation of eNOS from the cytosol to the endothelial cell membrane. We demonstrate that hyperpermeability is a self-limiting process, whose timed inactivation is an intrinsic property of the microvascular endothelium that maintains vascular homeostasis in response to inflammatory conditions. NEW & NOTEWORTHY Termination of microvascular hyperpermeability has been so far accepted to be a passive result of the removal of the applied proinflammatory agonists. We provide in vivo and in vitro evidence that 1) inactivation of hyperpermeability is an actively regulated process, 2) proinflammatory agonists (PAF and VEGF) stimulate microvascular hyperpermeability and initiate endothelial mechanisms that terminate hyperpermeability, and 3) eNOS location-translocation is critical in the activation-inactivation cascade of endothelial hyperpermeability.
登录
查看更多内容
影响因子：
3.3
作者：
Chen Z;D S Oliveira S;Zimnicka AM;Jiang Y;Sharma T;Chen S;Lazarov O;Bonini MG;Haus JM;Minshall RD
通讯作者：
Minshall RD
影响因子：
20.1
作者：
Marín N;Zamorano P;Carrasco R;Mujica P;González FG;Quezada C;Meininger CJ;Boric MP;Durán WN;Sánchez FA
通讯作者：
Sánchez FA
影响因子：
46.9
作者：
Fredriksson, S;Gullberg, M;Landegren, U
通讯作者：
Landegren, U
DOI：
10.1152/ajpheart.00370.2006
发表时间：
2006-09-01
影响因子：
4.8
作者：
Sanchez, Fabiola A.;Savalia, Nirav B.;Duran, Walter N.
通讯作者：
Duran, Walter N.
影响因子：
5.5
作者：
Figueroa, XF;González, DR;Boric, MP
通讯作者：
Boric, MP