Vascular permeability--the essentials

Abstract

The vasculature, composed of vessels of different morphology and function, distributes blood to all tissues and maintains physiological tissue homeostasis. In pathologies, the vasculature is often affected by, and engaged in, the disease process. This may result in excessive formation of new, unstable, and hyperpermeable vessels with poor blood flow, which further promotes hypoxia and disease propagation. Chronic vessel permeability may also facilitate metastatic spread of cancer. Thus, there is a strong incentive to learn more about an important aspect of vessel biology in health and disease: the regulation of vessel permeability. The current review aims to summarize current insights into different mechanisms of vascular permeability, its regulatory factors, and the consequences for disease.

Keywords: Edema; VEGF; histamine; junctions; pore; vascular permeability.

Figure 1.

Different mechanisms for extravasation of solute, cells, and molecules. Specialized capillaries in endocrine organs have pores, fenestrae, in the plasma membrane. Fenestrae allow rapid exchange of solute and molecules such as hormones. Transcellular gaps provide a route for inflammatory cells, which, however, also may exit through paracellular junctions. Disintegration of junctions allows extravasation of molecules.

Figure 2.

Opening of adherens junction in molecular extravasation. Panel A outlines schematically how VE-cadherin (VEC) engaged in hemophilic interactions at adherens junctions is regulated by hyperphosphorylation, correlating with internalization and degradation of VE-cadherin. VE-cadherin may also recycle; see text. Panel B shows leaky mouse tracheal vasculature after tail-vein injection of VEGF and fluorescent microspheres (white), followed by whole-mount immunostaining for VE-cadherin (red). VEGF-induced vascular leakiness leads to edema.

Figure 3.

Signal transduction regulating opening of adherens junctions. Three main pathways are depicted: 1) VEGF-induced activation of c-Src leading to VE-cadherin (VE-cad) hyperphosphorylation (pY); 2) activation of eNOS leading to NO generation and effects on adherens junctions; and 3) activation of small GTPases such as RAC followed by rearrangement of the actin cytoskeleton and cell retraction. For details, see text.