Vascular Permeability in Diseases

Abstract

Vascular permeability is a selective mechanism that maintains the exchange between vessels, tissues, and organs. The regulation was mostly studied during the nineteenth century by physiologists who defined physical laws and equations, taking blood, tissue interstitial, and oncotic pressure into account. During the last decades, a better knowledge of vascular cell functions and blood-vessel interactions opens a new area of vascular biology. Endothelial cell receptors vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule (ICAM), vascular endothelial growth factor receptor (VEGFR-2), receptor for advanced glycation end products (RAGE), and mediators were identified and their role in homeostasis and pathological situations was described. The molecular differences of endothelial cell junctions (tight, gap, and adherens junctions) and their role in vascular permeability were characterized in different organs. The main mediators of vasomotricity and permeability, such as prostaglandins, nitric oxide (NO), prostacyclin, vascular growth factor (VEGF), and cytokines, have been demonstrated to possess major functions in steady state and pathological situations. Leukocytes were shown to adhere to endothelium and migrate during inflammatory situations and infectious diseases. Increased vascular permeability is linked to endothelium integrity. Glycocalyx, when intact, may limit cancer cell metastasis. Biological modifications of blood and tissue constituents occurring in diabetes mellitus were responsible for increased permeability and, consequently, ocular and renal complications. Vascular pressure and fluidity are major determinants of pulmonary and cerebral edema. Beside the treatment of the infectious disease, of the blood circulation dysfunction and inflammatory condition, drugs (cyclooxygenase inhibitors) and specific antibodies anti-cytokine (anti-VEGF) have been demonstrated to reduce the severity and the mortality in diseases that exhibited enhanced vascular permeability.

Keywords: cerebral edema; diabetic vasculopathy; endothelial cells; endothelial junctions; macular edema; nitric oxide; prostacyclin; vascular endothelial cell growth factor; vascular permeability.

Figure 1

Endothelial cell junctions. Endothelial cells linked one to the other by different types of junctions form a barrier. Tight junctions: claudins, occludins, junction adhesion molecule (JAMs), endothelial cell-selective adhesion molecule (ESAM), and nectin. Gap junctions: connexins. Adherens junctions: nectin, VE-cadherin.

Figure 2

Vessel wall and glycocalyx. EC are in close proximity to smooth muscle cells (SMC) and pericytes, which, via mediators, have a continuous cross talk. EC are covered on the inner site by the glycocalyx. They expose the tissue factor, which can initiate coagulation. The receptors involved in leukocyte adhesion, such as the vascular adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM), are modulated by cytokines tumor necrosis factor α (TNFα), interleukin-1 (IL-1), interferon γ (IFNγ). The vascular endothelial growth factor (VEGF) and receptor VEGFR-2 induce VE-cadherin phosphorylation and junction opening.

Figure 3

Modulation of vascular permeability and inflammation. Activated EC produced and released interleukin-6 (IL-6) and macrophage (monocyte) protein-1 (MCP-1) in inflammatory conditions. Advanced glycation end products (AGE), present on protein or red blood cell (RBC), bind to a specific receptor (RAGE), inducing a cascade of reactions, resulting in an increased vascular permeability. Nitric oxide (NO) is one of the mediators for vascular tone and vascular permeability. Prostacyclin (PGI 2) modulates vascular pressure and permeability. Activated platelets, after adhesion to the matrix and von Willebrand factor (VWF), release thromboxane A2 (TXA2), which contributes to permeability regulation.