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Am J Physiol Heart Circ Physiol (September 26, 2002). doi:10.1152/ajpheart.01118.2001
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Articles in PresS, published online ahead of print September 26, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.01118.2001
Submitted on December 20, 2001
Accepted on September 24, 2002

Epoxygenase driven angiogenesis in human lung microvascular endothelial cells

Meetha M Medhora1*, John Daniels1, Kavita Mundey1, Beate Fisslthaler1, Rudi Busse2, Elizabeth R Jacobs3, and David R Harder4

1 Department of Medicine, Division of Pulmonary and Critical Care, Milwaukee, WI, USA
2 Institut fur Kardiovaskulare Physiologie, Klinikum der Johann Wolfgang Goethe-Universtitat, Milwaukee, Germany
3 Department of Medicine, Division of Pulmonary and Critical Care, Milwaukee, WI, USA; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Frankfurt, WI, USA
4 Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Frankfurt, WI, USA

* To whom correspondence should be addressed. E-mail: medhoram{at}mcw.edu.

Angiogenesis is one of the most recent physiological functions attributed to products of cytochrome P450 (CYP450) enymes. To test this at a molecular level in human cells we used a cloned cDNA for the human endothelial enzyme CYP2C9 to study growth as well as differentiation of human microvascular endothelial cells from the lung (HMVEC-L). Using adenoviral vectors over-expressing mRNA for CYP2C9, we show that presence of CYP2C9 doubles thymidine incorporation and stimulates proliferation of primary cultures of endothelial cells as compared to Ad5-GFP (control) in 24 hours. In addition there is a significant increase of tube formation in matrigel after infection of HMVEC-L with Ad5-2C9 than with Ad5-GFP. More interestingly Ad5-2C9 expressing the antisense product of CYP2C9 (2C9AS) inhibited tube formation as compared to both Ad5-GFP as well as the Ad5-2C9 constructs. Finally we tested the most abundant arachidonic acid metabolite of CYP2C9, 14,15-EET, which induced angiogenesis in vivo, when embedded in matrigel plugs and implanted in adult rats. These data support an important role for CYP2C9 in promoting angiogenesis.




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