Barrier Maintenance in Neovessels - Mechanical and Chemical Signaling in Angiogenesis - page 218

which is kept in its active state by binding to IQGAP1. In addition, cadherin
engagement induces the activation of RapGEF2. This stimulates Rap1, which via
Vav2 activates Rac1. Rac1 activation results in the inhibition of p115RhoGEF and
thus a suppression of RhoA. Vav2 activity is further enhanced by p120ctn binding
to the junctional complexes. The latter also directly activates p190RhoGAP
thereby further inhibiting RhoA activity [ 26 ]. This signalling is controlled by
circulating barrier promoting factors such as FGF, S1P and Ang1.
Recent data indicate that stiffening of the vascular wall might destabilize the
endothelial barrier. Modulation of ECM properties bare impact on cell-ECM
traction forces, consequently altering cell-cell tension. This relationship between
ECM stiffness and endothelial permeability suggests that differences in local tissue
compliance might contribute to differences in permeability observed in different
parts of the vascular bed, such as seen in the lung (and brain) of which the tissue is
soft, and where the barrier is tighter than at other places.
Moreover, it remains to be tested whether destiffening strategies would provide
an effective means to combat diseases where vascular stiffening and vascular leak
go hand in hand. Pharmacological treatment of stiffness of the vascular wall
appears impossible. Attempts have been made with various drugs, including
advanced glycation end-product crosslinking breakers, aimed to restore elasticity
to the disorganized elastic fibers of the thoracic aorta [ 45 , 46 ]. However, there
is presently little evidence that these agents actually break pre-existing cross-links
in vivo. Conversely, drugs currently used to treat arterial stiffness have effects on
muscular arteries, and these dilate by C20 % with relatively small doses, but do
not affect elastic arteries such as the proximal aorta and carotid artery. As therapies
aimed at vasodilation do not directly target the structural composition of the
vasculature, it is to be expected that they will have limited value in improving the
integrity of the vascular barrier. Preventing the endothelial cells from responding
to the stiffening through lowering of basal traction forces, and thus lowering of
junctional tension, might provide a more promising approach to stabilize the
vascular barrier in a stiffening microenvironment.
References
1. Nagy, J.A., Dvorak, A.M., Dvorak, H.F.: Vascular hyperpermeability, angiogenesis, and
stroma generation. Cold Spring Harb Perspect Med. 2(2), a006544 (2012)
2. van Hinsbergh, V.W, van Nieuw Amerongen, G.P.: Intracellular signalling involved in
modulating human endothelial barrier function. J. Anat. 200(6), 549-560 (2002)
3. Krishnan, R., Klumpers, D.D., Park, C.Y., Rajendran, K., Trepat, X., van Bezu, J., van
Hinsbergh, V.W., Carman, C.V., Brain, J.D., Fredberg J.J., Butler, J.P., van Nieuw
Amerongen, G.P.: Substrate stiffening promotes endothelial monolayer disruption through
enhanced physical forces. Am. J. Physiol. Cell Physiol. 300(1), C146-C154 (2011)
4. Mehta, D., Malik, A.B.: Signaling mechanisms regulating endothelial permeability. Physiol.
Rev. 86(1), 279-367 (2006)
5. Goldenberg, N.M., Steinberg, B.E., Slutsky, A.S., Lee WL.: Broken barriers: a new take on
sepsis pathogenesis. Sci. Transl. Med. 3(88):88ps25 (2011)