Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth.

Xia, Pu; Aiello, Lloyd Paul; Ishii, Hiromichi; Jiang, Zhaoxin; Park, Dong Ho; Robinson, G. A.; Takagi, Hitoshi; Newsome, William; Jirousek, Michael R.; King, George L.

doi:10.1172/jci119006

Cited by 525 publications

(362 citation statements)

References 39 publications

(41 reference statements)

Supporting

Mentioning

339

Contrasting

Unclassified

Order By: Relevance

“…Although the specific roles of its different isoforms have not been fully clarified, the α and β isoforms seem to be specifically implicated in cell proliferation [7]. PKC-β2, in particular, mediates the angiogenic and permeability-enhancing effects of vascular endothelial growth factor-vascular permeability factor (VEGF-VPF), involved in sight-threatening diabetic retinopathy [8]. Evidence for a central role of PKC in diabetic macular oedema and proliferative retinopathy led to develop specific β isoform inhibitors for therapeutic purposes.…”

Section: Discussionmentioning

confidence: 99%

Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes

et al. 2003

View full text Add to dashboard Cite

Aims/hypothesis. Drop-out of capillary pericytes occurs early and selectively in diabetic retinopathy. High glucose concentrations decrease replication and increase apoptosis of cultured pericytes. Since glucose activates protein kinase C, we investigated the effects of modulating this intracellular mediator on replication, cell cycle and apoptosis of cultured bovine retinal pericytes. Methods. Pericytes cultured in 5.6 or 28 mmol/l glucose were exposed to a protein kinase C activator (phorbol 12-myristate 13-acetate) and/or a selective inhibitor of its β2 isoform (LY379196). Cells were counted after 7 days. Proliferation by the tetrazolium to formazan assay and DNA synthesis by 5-bromo-2′-deoxyuridine incorporation were measured at day 4. Cell cycle by flow cytometry and apoptosis by ELISA were assessed at day 2. Results. High glucose reduced pericyte replication and increased apoptosis. Protein kinase C activation increased proliferation, while inhibition of its β2 isoform decreased it. Cell cycle was accelerated by protein kinase C activation and delayed by inhibition. Apoptosis was enhanced by protein kinase C inhibition and reduced by activation. Conclusions/interpretation. Protein kinase C inhibition amplifies the anti-proliferative and pro-apoptotic effects of high glucose on cultured pericytes, whereas stimulation reduces apoptosis and promotes proliferation both in physiological glucose and high glucose. Protein kinase C inhibition, proposed for the treatment of diabetic macular edema and proliferative retinopathy, might accelerate pericyte dropout in earlier stages when these cells are still present in retinal capillaries. [Diabetologia (2003) 46:416-419]

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes

et al. 2003

View full text Add to dashboard Cite

show abstract

“…However, it was reported recently that in liver sinusoidal endothelial cells the VEGF growth signal is transduced mostly through PLCg-PKC and not via Ras (Takahashi et al, 1999). Phosphorylated VEGFR-2 rapidly recruits and activates PLCg (Waltenberger et al, 1994;D'Angelo et al, 1995;Guo et al, 1995;Xia et al, 1996;Takahashi and Shibuya, 1997) which then hydrolyses a cell membrane phospholipid, phosphatidyl inositol 4,5-bisphosphate, and releases sn-1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). These two second messengers are responsible for direct activation of certain PKC isoforms and for the release of Ca 2+ from intracellular stores, respectively (Criscuolo et al, 1989;Brock et al, 1991;de Vries et al, 1992).…”

Section: Vegfr-2mentioning

confidence: 99%

“…These two second messengers are responsible for direct activation of certain PKC isoforms and for the release of Ca 2+ from intracellular stores, respectively (Criscuolo et al, 1989;Brock et al, 1991;de Vries et al, 1992). VEGF has been shown to selectively activate the Ca 2+ -sensitive PKC isoforms g and b2 in bovine aortic endothelial cells (Xia et al, 1996;Takahashi et al, 1999) and PKCe in HUVE cells (Wu et al, 2000). In the former case the mitogenic e ect of VEGF in endothelial cells was suppressed by PKC-b and -gselective inhibitors.…”

Section: Vegfr-2mentioning

confidence: 99%

Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis

2000

View full text Add to dashboard Cite

“…65 PLC g activation leads to increases in diacylglycerol and subsequent activation of classical forms of PKC, especially the bII and d isoforms. 66 Experimental work has demonstrated that selective inhibition of the PKC b isoform prevents VEGF-mediated cell growth in vitro, 57 while inhibition of the PKC a isoform stimulates growth.…”

Section: Blockade Of Signal Transduction Pathwaysmentioning

confidence: 99%

Growth factors and protein kinase C inhibitors as novel therapies for the medical management diabetic retinopathy

Aiello

Cahill

Cavallerano

2004

Eye

Self Cite

View full text Add to dashboard Cite

Diabetic retinopathy is a leading cause of acquired visual loss. Current treatment modalities are not effective in all cases and may have side effects. Investigation of the biochemical basis of diabetic retinopathy suggests that future treatments may reverse or halt the progression of diabetic retinopathy, or actually prevent the development of diabetic retinopathy. Pharmacological manipulation of protein kinase C and various growth factors may form the basis of future treaments for diabetic retinopathy.

show abstract

Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth.

Cited by 525 publications

References 39 publications

Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes

Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes

Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis

Growth factors and protein kinase C inhibitors as novel therapies for the medical management diabetic retinopathy

Contact Info

Product

Resources

About