McDonald D M
Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, California 94143-0130, USA.
Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 2):S39-45. doi: 10.1164/ajrccm.164.supplement_2.2106065.
Angiogenesis and microvascular remodeling are known features of chronic inflammatory diseases such as asthma and chronic bronchitis, but the mechanisms and consequences of the changes are just beginning to be elucidated. In a model of chronic airway inflammation produced by Mycoplasma pulmonis infection of the airways of mice or rats, angiogenesis and microvascular remodeling create vessels that mediate leukocyte influx and leak plasma proteins into the airway mucosa. These vascular changes are driven by the immune response to the organisms. Plasma leakage results from gaps between endothelial cells, as well as from increased vascular surface area and probably other changes in the newly formed and remodeled blood vessels. Treatment with long-acting beta2 agonists can reduce but not eliminate the plasma occurring after infection. In addition to the elevated baseline leakage, the remodeled vessels in the airway mucosa are abnormally sensitive to substance P, but not to platelet-activating factor or serotonin, suggesting that the infection leads to a selective upregulation of NK1 receptors on the vasculature. The formation of new vessels and the remodeling of existing vessels are likely to be induced by multiple growth factors, including vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). VEGF increases vascular permeability, but Ang1 has the opposite effect. This feature is consistent with evidence that VEGF and Ang1 play complementary and coordinated roles in vascular growth and remodeling and have powerful effects on vascular function. Regulation of vascular permeability by VEGF and Ang1 may be their most rapid and potent actions in the adult, as these effects can occur independent of their effects on angiogenesis and vascular remodeling. The ability of Ang1 to block plasma leakage without producing angiogenesis may be therapeutically advantageous. Furthermore, because VEGF and Ang1 have additive effects in promoting angiogenesis but opposite effects on vascular permeability, they could be used together to avoid the formation of leaky vessels in therapeutic angiogenesis. Finally, the elucidation of the protective effect of Ang1 on blood vessel leakiness to plasma proteins raises the possibility of a new strategy for reducing airway edema in inflammatory airway diseases such as asthma and chronic bronchitis.
血管生成和微血管重塑是诸如哮喘和慢性支气管炎等慢性炎症性疾病的已知特征，但这些变化的机制和后果才刚刚开始得到阐明。在由肺炎支原体感染小鼠或大鼠气道所产生的慢性气道炎症模型中，血管生成和微血管重塑会形成介导白细胞流入并使血浆蛋白渗漏到气道黏膜中的血管。这些血管变化是由对病原体的免疫反应驱动的。血浆渗漏源于内皮细胞之间的间隙，以及血管表面积增加，可能还有新形成和重塑血管的其他变化。长效β2激动剂治疗可减少但不能消除感染后出现的血浆渗漏。除了基线渗漏升高外，气道黏膜中重塑的血管对P物质异常敏感，但对血小板活化因子或5-羟色胺不敏感，这表明感染导致血管系统上NK1受体的选择性上调。新血管的形成和现有血管的重塑可能由多种生长因子诱导，包括血管内皮生长因子（VEGF）和血管生成素1（Ang1）。VEGF增加血管通透性，但Ang1具有相反的作用。这一特征与VEGF和Ang1在血管生长和重塑中发挥互补和协调作用并对血管功能有强大影响的证据一致。VEGF和Ang1对血管通透性的调节可能是它们在成体中最快速和最有效的作用，因为这些作用可以独立于它们对血管生成和血管重塑的影响而发生。Ang1在不产生血管生成的情况下阻断血浆渗漏的能力可能具有治疗优势。此外，由于VEGF和Ang1在促进血管生成方面具有相加作用，但对血管通透性具有相反作用，它们可以一起使用以避免在治疗性血管生成中形成渗漏血管。最后，对Ang1对血浆蛋白血管渗漏的保护作用的阐明，为减少诸如哮喘和慢性支气管炎等炎症性气道疾病中的气道水肿提供了一种新策略的可能性。
