Relative or absolute hypoxia activates signaling pathways that alter gene expression and stabilize the pulmonary microvasculature. Alveolar hypoxia occurs in disorders ranging from altitude sickness to airway obstruction, apnea, and atelectasis. Here, we report that the phospholipid-binding protein, annexin A2 (ANXA2) functions to maintain vascular integrity in the face of alveolar hypoxia. We demonstrate that microvascular endothelial cells (ECs) from Anxa2^−/− mice display reduced barrier function and excessive Src-related tyrosine phosphorylation of the adherens junction protein vascular endothelial cadherin (VEC). Moreover, unlike Anxa2^+/+ controls, Anxa2^−/− mice develop pulmonary edema and neutrophil infiltration in the lung parenchyma in response to subacute alveolar hypoxia. Mice deficient in the ANXA2-binding partner, S100A10, failed to demonstrate hypoxia-induced pulmonary edema under the same conditions. Further analyses reveal that ANXA2 forms a complex with VEC and its phosphatases, EC-specific protein tyrosine phosphatase (VE-PTP) and Src homology phosphatase 2 (SHP2), both of which are implicated in vascular integrity. In the absence of ANXA2, VEC is hyperphosphorylated at tyrosine 731 in response to vascular endothelial growth factor, which likely contributes to hypoxia-induced extravasation of fluid and leukocytes. We conclude that ANXA2 contributes to pulmonary microvascular integrity by enabling VEC-related phosphatase activity, thereby preventing vascular leak during alveolar hypoxia.

相对或绝对缺氧会激活信号通路，从而改变基因表达并稳定肺微血管。肺泡缺氧发生在各种疾病中，从高原反应到气道阻塞，呼吸暂停和肺不张。在这里，我们报道磷脂结合蛋白，膜联蛋白A2（ANXA2）的功能是维持面对肺泡缺氧的血管完整性。我们证明了从Anxa2 ^-/-小鼠的微血管内皮细胞（EC）显示减少的屏障功能和粘附连接蛋白血管内皮钙黏着蛋白（VEC）的过量Src相关酪氨酸磷酸化。此外，与Anxa2 ^{+ / +}控件不同，Anxa2 ^-/-对亚急性肺泡缺氧的反应，小鼠在肺实质中出现肺水肿和中性粒细胞浸润。在相同条件下，缺乏ANXA2结合伴侣S100A10的小鼠未能表现出低氧诱导的肺水肿。进一步的分析表明，ANXA2与VEC及其磷酸酶，EC特异性蛋白酪氨酸磷酸酶（VE-PTP）和Src同源磷酸酶2（SHP2）形成复合物，两者均与血管完整性有关。在缺乏ANXA2的情况下，VEC在酪氨酸731处对血管内皮生长因子产生了过度磷酸化，这可能有助于缺氧诱导的液体和白细胞外渗。我们得出的结论是，ANXA2通过启用VEC相关的磷酸酶活性来促进肺微血管完整性，从而防止肺泡缺氧时的血管渗漏。