Caveolae are prominent plasmalemmal invaginations in endothelial cells, especially in the lung vasculature, which comprises a vast surface area. PV1 (plasmalemmal vesicle–associated protein-1), a 60-kD glycoprotein expressed in endothelial cells, is essential for generating spoke-like diaphragmatic structures that span the neck region of endothelial caveolae. However, their role in caveolae-mediated uptake and endothelial-barrier function is unknown. Here, we generated mice with endothelial cell–specific deletion of PV1 through tamoxifen-induced Cdh5.Cre.ERT2 (endothelial-specific vascular cadherin.Cre.estrogen receptor 2)-mediated excision of the floxed PV1 allele. We observed that loss of PV1 specifically in endothelial cells increased lung vascular permeability of fluid and protein, indicating that PV1 is required for maintenance of lung vascular-barrier integrity. Endothelial-specific PV1 deletion also increased caveolae-mediated uptake of tracer albumin compared with controls, promoted Au-albumin accumulation in the bulb of caveolae, and induced caveolar swelling. In addition, we observed the progressive loss of plasma proteins from the circulation and reduced arterial pressure resulting from transudation of water and protein as well as edema formation in multiple tissues, including lungs. These changes seen after endothelial-specific PV1 deletion occurred in the absence of disruption of endothelial junctions. We demonstrated that exposure of wild-type mice to endotoxin, which is known to cause acute lung injury and increase protein permeability, also significantly reduced PV1 protein expression. We conclude that the key function of PV1 is to regulate lung endothelial permeability through its ability to restrict the entry of plasma proteins such as albumin into caveolae and their transport through the endothelial barrier.

小窝是内皮细胞中突出的质膜内陷，特别是在肺血管系统中，其包括广阔的表面积。PV1（浆膜囊泡相关蛋白-1）是一种在内皮细胞中表达的 60kD 糖蛋白，对于产生跨越内皮细胞小窝颈部区域的轮辐状隔膜结构至关重要。然而，它们在小窝介导的吸收和内皮屏障功能中的作用尚不清楚。在这里，我们通过他莫昔芬诱导的 Cdh5.Cre.ERT2（内皮特异性血管钙粘蛋白.Cre.estrogen 受体 2）介导的 floxed PV1 等位基因切除，产生了具有内皮细胞特异性 PV1 缺失的小鼠。我们观察到内皮细胞中 PV1 的缺失增加了肺血管液体和蛋白质的渗透性，表明 PV1 是维持肺血管屏障完整性所必需的。与对照相比，内皮特异性 PV1 缺失也增加了细胞膜穴样凹陷介导的示踪白蛋白的摄取，促进了细胞膜穴样凹陷球部中金白蛋白的积累，并诱导了细胞穴样肿胀。此外，我们观察到血浆蛋白质从循环中逐渐丢失，水和蛋白质渗出导致的动脉压降低，以及包括肺在内的多个组织中的水肿形成。内皮特异性 PV1 缺失后发生的这些变化在内皮连接没有破坏的情况下发生。我们证明野生型小鼠暴露于已知会导致急性肺损伤和增加蛋白质通透性的内毒素，也会显着降低 PV1 蛋白的表达。