Endogenous endothelial cell signaling systems maintain vascular stability - PubMed (original) (raw)
Review
Endogenous endothelial cell signaling systems maintain vascular stability
Nyall R London et al. Angiogenesis. 2009.
Abstract
The function of the endothelium is to provide a network to allow delivery of oxygen and nutrients to tissues throughout the body. This network comprises adjacent endothelial cells that utilize adherens junction proteins such as vascular endothelial cadherin (VE-cadherin) to maintain the appropriate level of vascular permeability. The disruption of VE-cadherin interactions during pathologic settings can lead to excessive vascular leak with adverse effects. Endogenous cell signaling systems have been defined, which help to maintain the proper level of vascular stability. Perhaps the best described system is Angiopoietin-1 (Ang-1). Ang-1 acting through its receptor Tie2 generates a well-described set of signaling events ultimately leading to enhanced vascular stability. In this review, we will focus on what is known about additional endogenous cell signaling systems that stabilize the vasculature, and using Ang-1/Tie2 as a model, we will address where our understanding of these additional systems is lacking.
Figures
Figure 1. VE-cadherin interactions are disrupted by phosphorylation and endocytosis
(a) Under normal conditions, VE-cadherin forms tight interactions that inhibit excessive vascular leak. (b) Kinases such as Src can phosphorylate the cytoplasmic tail of VE-cadherin, resulting in the disruption of VE-cadherin interactions and increased vascular permeability. (c) VE-cadherin interactions are also disrupted through endocytosis, resulting in increased vascular leak. The binding of p-120 catenin to the cytoplasmic tail of VE-cadherin inhibits internalization resulting in enhanced vascular stability.
Figure 2. Endogenous cell signaling systems decrease vascular hyperpermeability
(top) VEGF disrupts the barrier function of the endothelium resulting in enhanced vascular leak. (bottom) Cell signaling systems such as Slit-Robo4, Ang-1-Tie2, and Dll4-Notch stabilize the vasculature.
Figure 3. Endogenous cell signaling systems enhance vascular stability
(a) VEGF disrupts VE-cadherin interactions through activation of Src resulting in the phosphorylation of the cytoplasmic tail of VE-cadherin. (b) Ang-1 through its receptor Tie2 activates Rho. This causes the activation of mDia, which sequesters Src resulting in the inhibition of Src and stabilization of VE-cadherin. (c) Dll4 binds Notch resulting in the cleavage of the NICD and its transfer to the nucleus. The resulting signaling events that affect endothelial cell junctional stability are unknown. (d) Slit through a Robo4 dependent mechanism inhibits VEGF-induced activation of Src. The signaling events from Robo4 to Src are unknown.
Figure 4. The CCM genes define an intracellular protein complex promoting vascular stability
The three genes associated with cerebral cavernous malformations (KRIT1, CCM2, and PDCD10) interact with each other and a variety of other intracellular and cell surface proteins to enhance the stability of endothelial cell junctions and the cellular cytoskeleton. As described in the text, such interactions include the Heart of glass (HEG) cell surface receptor, ß-catenin (ß-cat), small GTPases including RAP1 and Rho family GTPases, and proteins of MAP kinase signaling cascades.
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