VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling

Kalpna Gupta, Smita Kshirsagar, Wei Li, Lizhen Gui, Sundaram Ramakrishnan, Pankaj Gupta, Ping-Yee Law, Robert P Hebbel

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349 Scopus citations


Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, promotes endothelial cell survival and angiogenesis. We recently showed that VEGF can support the growth of human derreal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells in serum-free medium. Reasoning that VEGF might be modulating apoptotic signal transduction pathways, we examined mechanisms involved in the anti-apoptotic effect of VEGF on starvation- and ceramide-induced apoptosis in HDMEC. We observed that VEGF ameliorated the time-dependent increase in apoptosis, as demonstrated by morphologic observations, TUNEL assay, and DNA fragmentation. On the other hand, basic fibroblast growth factor only partially prevented apoptosis in serum-starved HDMEC; platelet-derived growth factor-BB was completely ineffective. VEGF activated the phosphorylation of extracellular signal regulated kinase (ERK)1 (p44 mitogen-activated protein kinase; MAPK) and ERK2 (p42 MAPK) in a time- and concentration-dependent manner. Both the VEGF-induced activation and its anti-apoptotic effect were prevented by the specific MAPK/ERK inhibitor PD98059. The presence of VEGF also inhibited the sustained activation of stress-activated protein kinase/c-jun-NH2-kinase (SAPK/JNK) caused by serum starvation and cer- amide treatment. Activation of the MAPK pathway together with inhibition of SAPK/JNK activity by VEGF appears to be a key event in determining whether an endothelial cell survives or undergoes programmed cell death.

Original languageEnglish (US)
Pages (from-to)495-504
Number of pages10
JournalExperimental Cell Research
Issue number2
StatePublished - Mar 15 1999

Bibliographical note

Funding Information:
1This work was supported by NIH Grants HL30160 (to R.P.H.) and CA73871 (to S.R.). 2To whom reprint requests should be addressed at Division of Hematology, Oncology and Transplantation, Department of Medicine, Box 480 UMHC, 420 Delaware Street SE, Minneapolis, MN 55455. Fax: (612) 625-6919. E-mail:


  • Angiogenesis
  • Apoptosis
  • ERK
  • Endothelium
  • JNK
  • MAPK
  • SAPK
  • VEGF


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