Barrier Maintenance in Neovessels - Mechanical and Chemical Signaling in Angiogenesis - page 213

constitutive caveolin-1-dependent inhibition of eNOS activity. Deficiency in
caveolin-1 or activation of eNOS results in nitration of p190RhoGAP and the con-
comitant activation of RhoA, which induces adherens junction destabilization and
increased endothelial permeability. Because of the causal relationship of eNOS-
specific signaling to the impairment of p190RhoGAP activity, this mechanism
induces RhoA activation in endothelial cells [ 30 ].
Taken together, these data indicate that caveolin-1 mediated signaling is critical
in mediating the increased permeability of the vascular junctional endothelial
barrier secondary to AJ disassembly; i.e., there is signaling cross-talk between
caveolae-mediated endocytosis and junctional permeability.
3.3 Regulation by Soluble Mediators
Many vaso-active agents are known to cause plasma leakage by increasing
vascular permeability, but only a few soluble mediators are known to possess the
opposite characteristics. Currently known endogenous barrier improving mole-
cules include sphingosine 1-phosphate (S1P), adrenomedullin, Angiopoietin-1
(Ang1), Fibroblast Growth Factor (FGF), nitric oxide and adenosine [ 32 ].
Therapeutic efforts to enhance their function hold promise for the future because
those compounds will likely be exploited in their ability to induce recovery of
disturbed barrier functions and to act as prophylactic in stabilizing vascular
barriers. The most prominent soluble mediators of endothelial barrier maintenance
are discussed below.
3.3.1 Angiopoietins
The angiopoietin-Tie2 signaling system plays a crucial role in regulating endo-
thelial barrier maintenance [ 33 - 35 ]. Ang-1 is a ligand of the endothelial cell
receptor Tie2, and activation of Tie2 signaling enhances endothelial cell barrier
integrity and endothelial-pericyte interaction, thereby promoting vascular stabil-
ization. While expression of Tie2 is largely specific to the endothelium, Ang-1
production by mural and perivascular cells facilitates basal Tie2 signaling in qui-
escent endothelial cells that, in turn, is required for endothelial homeostasis.
In contrast, Ang-2, produced and stored in Weibel-Palade bodies in endothelial
cells, normally functions as an Ang-1 antagonist. Ang-2 destabilizes the quiescent
vasculature and activates endothelial cells to respond to angiogenic stimuli [ 33 ].
Overexpression of Ang-2 in the mouse endothelium attenuates physiological Tie2
signaling and thus increases vascular permeability, suggesting that Ang-2 inhibits
Tie2 signaling and counteracts the action of Ang-1 [ 34 ]. Consistent with these
experimental data, circulating Ang-2 is related to vascular permeability and
pulmonary dysfunction in critically ill patients [ 34 ].