In vivo mechanisms of vascular endothelial growth factor-mediated increased hydraulic conductivity of Rana capillaries

T. M. Pocock, D. O. Bates

    Research output: Contribution to journalArticlepeer-review

    Abstract

    1. Vascular endothelial growth factor (VEGF) increases hydraulic conductivity (Lp) in vivo. To determine the signal transduction cascade through which this is mediated, we measured the effect of inhibition of various signalling pathways on VEGF-mediated acute increases in Lp in individually perfused frog mesenteric microvessels. 2. VEGF receptors have previously been shown to activate phospholipase C-γ (PLCγ), protein kinase C (PKC) and MEK, the mitogen-activated and extracellular signal-related kinase (ERK) kinase. To determine the role of these signalling pathways we measured the effects of inhibitors of each on the VEGF-mediated increase in Lp. 3. VEGF-mediated increases in Lp were attenuated by pre-treatment with the PLC inhibitor U73122, but not affected by treatment with the inactive enantiomer U73343. The PLC inhibitor was also able to attenuate the increase in Lp mediated by the inflammatory mediator ATP. 4. Inhibition of either PKC or MEK activation using the selective inhibitors bisindolylmaleimide (BIM, 1 μM) and PD98059 (30 μM), respectively, did not change the VEGF-mediated increase in Lp. However, PD98059, BIM and U73122 all reduced phosphorylation of ERK1/2 determined by Western blot analysis with anti-phospho-ERK1/2 antibodies. 5. Furthermore, inhibition of the conversion of diacyl glycerol (DAG) to arachidonic acid, by perfusion with the DAG lipase inhibitor RHC80267 (50 μM), did not attenuate the increase in Lp brought about by VEGF. 6. These data suggest that VEGF acutely increases microvascular permeability in vivo through a mechanism that is dependent on PLC stimulation, but is independent of PKC or MEK activation or production of arachidonic acid from DAG. We therefore propose that VEGF acutely acts to increase Lp through the direct actions of DAG, independently of PKC or arachidonic acid.
    Original languageEnglish
    Pages (from-to)479-488
    Number of pages9
    JournalJournal of Physiology
    Volume534
    Issue number2
    Publication statusPublished - 15 Jul 2001

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