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J. Biol. Chem., Vol. 277, Issue 2, 1047-1057, January 11, 2002

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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^*

Izumi Suzuma, Kiyoshi Suzuma, Kohjiro Ueki, Yasuaki Hata^§, Edward P. Feener, George L. King^¶, and Lloyd Paul Aiello^**

From the  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

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)- 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.

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