| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Microvascular Research Laboratories, Department of Physiology, University of Bristol, Bristol, United Kingdom
* To whom correspondence should be addressed. E-mail: Dave.Bates{at}bris.ac.uk.
Vascular endothelial growth factor (VEGF) increases vascular permeability by stimulating endothelial calcium influx. Here we provide evidence that links VEGF mediated increased permeability and endothelial calcium concentration ([Ca2+]i) with diacylglycerol (DAG) mediated activation of the transient receptor potential channels (TRPCs). We used the Landis-Michel technique to measure changes in hydraulic conductivity (Lp) and fluorescence photometry to measure changes in [Ca2+]i in individually perfused Rana mesenteric microvessels in vivo, and transfected non-endothelial cells in vitro. The membrane-permeant DAG analogue, 1-oleoyl-2-acetyl-sn-glycerol (OAG; 100µM), known to increase calcium influx through TRPC channels, transiently increased Lp 3.8 ± 1.2 fold (from 1.6 ± 0.8 to 9.8 ± 2.7 x 10-7 cm.s-1.cmH2O-1, p<0.0001; n=18). Protein kinase C inhibition by bisindolylmaleimide (BIM; 1µM) did not affect the OAG-induced increases in Lp. OAG also significantly increased microvascular endothelial [Ca2+]i in vivo (n=13; p<0.0001), which again was not sensitive to PKC inhibition. VEGF induced a transient increase in [Ca2+]i in human embryonic kidney cells (HEK293) co-transfected with VEGFR-2 and TRPC6, but not with control, VEGFR-2 or TRPC6 expression vector alone (p<0.01, n=9). Flufenamic acid, which has been shown to enhance TRPC6 activity, but inhibit TRPC3 and 7, enhanced the VEGF mediated increase in Lp in approximately half the vessels tested, but inhibited the response in the other half. These data provide evidence consistent with the hypothesis that VEGF increases vascular permeability through DAG mediated calcium entry through TRPC channels. Although the exact identities of the TRPC channels remain to be confirmed, TRPC6 appears to be a likely candidate in approximately half the vessels.
This article has been cited by other articles:
|
|
 |
|
  J. Abramowitz and L. Birnbaumer Physiology and pathophysiology of canonical transient receptor potential channels FASEB J, February 1, 2009; 23(2): 297 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Chaudhuri, S. M. Colles, M. Bhat, D. R. Van Wagoner, L. Birnbaumer, and L. M. Graham Elucidation of a TRPC6-TRPC5 Channel Cascade That Restricts Endothelial Cell Movement Mol. Biol. Cell, August 1, 2008; 19(8): 3203 - 3211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. N. Gavrilovskaya, E. E. Gorbunova, N. A. Mackow, and E. R. Mackow Hantaviruses Direct Endothelial Cell Permeability by Sensitizing Cells to the Vascular Permeability Factor VEGF, while Angiopoietin 1 and Sphingosine 1-Phosphate Inhibit Hantavirus-Directed Permeability J. Virol., June 15, 2008; 82(12): 5797 - 5806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-W. Cheng, A.F. James, R.R. Foster, J.C. Hancox, and D.O. Bates VEGF Activates Receptor-Operated Cation Channels in Human Microvascular Endothelial Cells Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1768 - 1776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Mehta and A. B. Malik Signaling Mechanisms Regulating Endothelial Permeability Physiol Rev, January 1, 2006; 86(1): 279 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Alvarez, J. A. King, and M. I. Townsley Resistance to Store Depletion-induced Endothelial Injury in Rat Lung after Chronic Heart Failure Am. J. Respir. Crit. Care Med., November 1, 2005; 172(9): 1153 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Yao and C. J. Garland Recent Developments in Vascular Endothelial Cell Transient Receptor Potential Channels Circ. Res., October 28, 2005; 97(9): 853 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Jho, D. Mehta, G. Ahmmed, X.-P. Gao, C. Tiruppathi, M. Broman, and A. B. Malik Angiopoietin-1 Opposes VEGF-Induced Increase in Endothelial Permeability by Inhibiting TRPC1-Dependent Ca2 Influx Circ. Res., June 24, 2005; 96(12): 1282 - 1290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Glass, T. M. Pocock, F. E. Curry, and D. O. Bates Cytosolic Ca2+ concentration and rate of increase of the cytosolic Ca2+ concentration in the regulation of vascular permeability in Rana in vivo J. Physiol., May 1, 2005; 564(3): 817 - 827. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
