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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/L676    most recent 00496.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Medhora, M. Articles by Jacobs, E. R. PubMed PubMed Citation Articles by Medhora, M. Articles by Jacobs, E. R.

Role of JNK in network formation of human lung microvascular endothelial cells

¹Division of Pulmonary and Critical Care, Department of Medicine, and ²Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 3 December 2007 ; accepted in final form 7 February 2008

The signaling mechanisms in vasculogenesis and/or angiogenesis remain poorly understood, limiting the ability to regulate growth of new blood vessels in vitro and in vivo. Cultured human lung microvascular endothelial cells align into tubular networks in the three-dimensional matrix, Matrigel. Overexpression of MAPK phosphatase-1 (MKP-1), an enzyme that inactivates the ERK, JNK, and p38 pathways, inhibited network formation of these cells. Adenoviral-mediated overexpression of recombinant MKP-3 (a dual specificity phosphatase that specifically inactivates the ERK pathway) and dominant negative or constitutively active MEK did not attenuate network formation in Matrigel compared with negative controls. This result suggested that the ERK pathway may not be essential for tube assembly, a conclusion which was supported by the action of specific MEK inhibitor PD 184352, which also did not alter network formation. Inhibition of the JNK pathway using SP-600125 or L-stereoisomer (L-JNKI-1) blocked network formation, whereas the p38 MAPK blocker SB-203580 slightly enhanced it. Inhibition of JNK also attenuated the number of small vessel branches in the developing chick chorioallantoic membrane. Our results demonstrate a specific role for the JNK pathway in network formation of human lung endothelial cells in vitro while confirming that it is essential for the formation of new vessels in vivo.

mitogen-activated protein kinase; extracellular signal-regulated kinase; mitogen-activated protein kinase phosphatase; dominant negative mitogen-activated protein kinase-extracellular signal-regulated kinase kinase; PD 184352