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J. Biol. Chem., Vol. 277, Issue 2, 1047-1057, January 11, 2002
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From the Stretch-induced expression of
vascular endothelial growth factor (VEGF) is thought to be important in
mediating the exacerbation of diabetic retinopathy by systemic
hypertension. However, the mechanisms underlying stretch-induced VEGF
expression are not fully understood. We present novel findings
demonstrating that stretch-induced VEGF expression in retinal capillary
pericytes is mediated by phosphatidylinositol (PI) 3-kinase and protein kinase C (PKC)-
Stretch-induced Retinal Vascular Endothelial Growth Factor
Expression Is Mediated by Phosphatidylinositol 3-Kinase and Protein
Kinase C (PKC)-
but Not by Stretch-induced ERK1/2, Akt, Ras, or
Classical/Novel PKC Pathways*
,,,,¶, and
**
Research Division and
Beetham Eye Institute, Joslin Diabetes Center, Boston,
Massachusetts 02215, the § Department of Ophthalmology,
Kyushu University, Faculty of Medicine, Fukuoka 606-8507, Japan,
the ¶ Department of Medicine, Brigham & Women's Hospital, Boston,
Massachusetts 02215, and the ** Department of
Ophthalmology, Harvard Medical School, Boston, Massachusetts
02215
but is not mediated by ERK1/2, classical/novel isoforms of PKC, Akt, or Ras despite their activation by stretch. Cardiac profile cyclic stretch at 60 cpm increased VEGF mRNA
expression in a time- and magnitude-dependent manner
without altering mRNA stability. Stretch increased ERK1/2
phosphorylation, PI 3-kinase activity, Akt phosphorylation, and PKC-
activity. Signaling pathways were explored using inhibitors of PKC,
MEK1/2, and PI 3-kinase; adenovirus-mediated overexpression of
ERK, PKC-
, PKC-
, PKC-, and Akt; and dominant negative (DN)
mutants of ERK, PKC-, Ras, PI 3-kinase and Akt. Although stretch
activated ERK1/2 through a Ras- and PKC classical/novel
isoform-dependent pathway, these pathways were not
responsible for stretch-induced VEGF expression. Overexpression of DN
ERK and Ras had no effect on VEGF expression in these cells. In
contrast, DN PI 3-kinase as well as pharmacologic inhibitors of PI
3-kinase blocked stretch-induced VEGF
expression. Although stretch-induced PI 3-kinase activation increased
both Akt phosphorylation and activity of PKC-, VEGF expression was dependent on PKC- but not Akt. In addition, PKC- did not mediate stretch-induced ERK1/2 activation. These results suggest that stretch-induced expression of VEGF involves a novel mechanism dependent
upon PI 3-kinase-mediated activation of PKC- that is independent of
stretch-induced activation of ERK1/2, classical/novel PKC isoforms,
Ras, or Akt. This mechanism may play a role in the well documented
association of concomitant hypertension with clinical exacerbation of
neovascularization and vascular permeability.
*
This work was supported in part by National Institutes
of Health Grants EY-10827 (to L. P. A.), EY-5110 (to G. L. K.), and DK-48358 (to E. P. F.), the Juvenile Diabetes Research Foundation (to
L. P. A.), and the Research to Prevent Blindness Dolly Green Scholarship (to L. P. A.). The Joslin Diabetes Center is the
recipient of National Institutes of Health Diabetes and Endocrinology
Research Center Grant 36836.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Joslin Diabetes
Center, One Joslin Place, Boston, MA 02215. Tel.: 617-732-2427; Fax:
617-735-1960; E-mail: lpaiello@joslin.harvard.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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