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Am J Physiol Heart Circ Physiol (February 5, 2004). doi:10.1152/ajpheart.00786.2003
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Submitted on August 15, 2003
Accepted on December 30, 2003

Localization of VEGFR-2 and Phospholipase D2 in Endothelial Caveolae is Involved in VEGF-induced Phosphorylation of MEK and ERK

Chung-Hyun Cho1, Chang Sup Lee1, Mikyung Chang1, Il-Ho Jang1, Soo Jin Kim1, Inhwan Hwang1, Sung Ho Ryu1, Chin O Lee1, and Gou Young Koh1*

1 Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Korea, Republic of

* To whom correspondence should be addressed. E-mail: gykoh{at}postech.ac.kr.

To clarify the role of caveolae in vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2)-mediated signaling cascades, primary cultured human umbilical vein endothelial cells (HUVECs) were fractionated to isolate caveolae-enriched cell membranes. Interestingly, VEGFR-2, phospholipase D2 (PLD2), and Ras were enriched in caveolae-enriched fractions. Moreover, VEGF increased PLD activity in a time- and dose-dependent manner in HUVECs, while a ligand specific for VEGFR-1, placenta growth factor, did not change PLD activity. A PLD inhibitor, 1-butanol almost completely suppressed VEGF-induced ERK phosphorylation and cellular proliferation, while the negative control for 1-butanol, 3-butanol, did not produce significant changes. Addition of phosphatidic acid negated the 1-butanol-induced suppression. Pharmacological analyses using several inhibitors indicated that protein kinase C-{delta} (PKC-{delta} ) regulates the VEGF-induced activation of PLD/ERK. Thus, PLD2 could be involved in MEK/ERK signaling cascades that are induced by the VEGF/VEGFR- 2/PKC-{delta} pathway in endothelial cells. Pretreatment with the cholesterol depletion agent methyl-{beta}-cyclodextrin (M{beta} CD) almost completely disassembled caveolar structures, while addition of cholesterol to M{beta} CD-treated cells restored caveolar structures. Pretreatment with M{beta} CD largely abolished phosphorylation of MEK/ERK by VEGF, while addition of cholesterol restored VEGF-induced MEK/ERK phosphorylations. These results indicate that intact caveolae are required for the VEGF/VEGFR-2 mediated MEK/ERK signaling cascade.




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