Lillo Mauricio A, Burboa Pía C, Durán Walter N
Department of Pharmacology, Physiology and Neuroscience, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
J Cardiovasc Dev Dis. 2025 Sep 17;12(9):361. doi: 10.3390/jcdd12090361.
Endothelial hyperpermeability is a hallmark of diverse inflammatory and vascular pathologies, including sepsis, acute respiratory distress syndrome (ARDS), ischemia-reperfusion injury, and atherosclerosis. Traditionally considered a passive return to baseline following stimulus withdrawal, barrier recovery is now recognized as an active, endothelial-driven process. Earlier work identified individual components of this restorative phase, such as cyclic adenosine monophosphate (cAMP)/exchange protein directly activated by cAMP 1 (Epac1) signaling, Rap1/Rac1 activation, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and targeted cytoskeletal remodeling, as well as kinase pathways involving PKA, PKG, and Src. However, these were often regarded as discrete events lacking a unifying framework. Recent integrative analyses, combining mechanistic insights from multiple groups, reveal that nitric oxide (NO) generated early during hyperpermeability can initiate a delayed cAMP/Epac1 cascade. This axis coordinates Rap1/Rac1-mediated cortical actin polymerization, VASP-driven junctional anchoring, retro-translocation of endothelial nitric oxide synthase (eNOS) to caveolar domains, PP2A-dependent suppression of actomyosin tension, and Krüppel-like factor 2 (KLF2)-driven transcriptional programs that sustain endothelial quiescence. Together, these pathways form a temporally orchestrated, multi-tiered "inactivation" program capable of restoring barrier integrity even in the continued presence of inflammatory stimuli. This conceptual shift reframes NO from solely a barrier-disruptive mediator to the initiating trigger of a coordinated, pro-resolution mechanism. The unified framework integrates cytoskeletal dynamics, junctional reassembly, focal adhesion turnover, and redox/transcriptional control, providing multiple potential intervention points. Therapeutically, Epac1 activation, Rap1/Rac1 enhancement, RhoA/ROCK inhibition, PP2A activation, and KLF2 induction represent strategies to accelerate endothelial sealing in acute microvascular syndromes. Moreover, applying these mechanisms to arterial endothelium could limit low-density lipoprotein (LDL) entry and foam cell formation, offering a novel adjunctive approach for atherosclerosis prevention. In this review, we will discuss both the current understanding of endothelial hyperpermeability mechanisms and the emerging pathways of its active inactivation, integrating molecular, structural, and translational perspectives.
内皮细胞高通透性是多种炎症和血管疾病的标志，包括脓毒症、急性呼吸窘迫综合征（ARDS）、缺血再灌注损伤和动脉粥样硬化。屏障恢复传统上被认为是刺激撤除后被动恢复到基线水平的过程，现在被认为是一个由内皮细胞驱动的主动过程。早期的研究确定了这个恢复阶段的各个组成部分，如环磷酸腺苷（cAMP）/直接由cAMP 1激活的交换蛋白（Epac1）信号传导、Rap1/Rac1激活、血管舒张刺激磷蛋白（VASP）磷酸化、靶向细胞骨架重塑，以及涉及蛋白激酶A（PKA）、蛋白激酶G（PKG）和Src的激酶途径。然而，这些通常被视为缺乏统一框架的离散事件。最近的综合分析结合了多个研究小组的机制性见解，揭示了高通透性早期产生的一氧化氮（NO）可以启动延迟的cAMP/Epac1级联反应。这个轴协调Rap1/Rac1介导的皮质肌动蛋白聚合、VASP驱动的连接锚定、内皮型一氧化氮合酶（eNOS）向小窝结构域的逆向转位、蛋白磷酸酶2A（PP2A）依赖的肌动球蛋白张力抑制，以及维持内皮细胞静止的Krüppel样因子2（KLF2）驱动的转录程序。这些途径共同形成了一个时间上精心编排的多层“失活”程序，即使在炎症刺激持续存在的情况下也能够恢复屏障完整性。这一概念转变将NO从单纯的屏障破坏介质重新定义为协调的促消退机制的起始触发因素。这个统一的框架整合了细胞骨架动力学、连接重组、粘着斑周转以及氧化还原/转录控制，提供了多个潜在的干预点。在治疗方面，激活Epac1、增强Rap1/Rac1、抑制RhoA/ROCK、激活PP2A和诱导KLF2是加速急性微血管综合征中内皮细胞封闭的策略。此外，将这些机制应用于动脉内皮可以限制低密度脂蛋白（LDL）的进入和泡沫细胞的形成，为动脉粥样硬化的预防提供一种新的辅助方法。在这篇综述中，我们将从分子、结构和转化的角度，讨论目前对内皮细胞高通透性机制的理解以及其主动失活的新途径。
