Potential compensation among group I PAK members in hindlimb ischemia and wound healing

Laila Elsherif, Mehmet Ozler, Mohamed A. Zayed, Jessica H. Shen, Jonathan Chernoff, James E. Faber, Leslie V. Parise

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

PAKs are serine/threonine kinases that regulate cytoskeletal dynamics and cell migration. PAK1 is activated by binding to the small EF hand protein, CIB1, or to the Rho GTPases Rac1 or Cdc42. The role of PAK1 in angiogenesis was established based only on in vitro studies and its role in angiogenesis in vivo has never been examined. Here we tested the hypothesi s that PAK1 is an essential regulator of ischemic neovascularization (arteriogenesis and angiogenesis) and wound healing using a global PAK1 knockout mouse. Neovascularization was assessed using unilateral hindlimb ischemia. We found that plantar perfusion, limb use and appearance were not significantly different between 6-8 week old PAK12/2 and PAK1+/+ mice throughout the 21-day period following hindlimb ischemia; however a slightly delayed healing was observed in 16 week old PAK12/2 mice. In addition, the wound healing rate, as assessed with an ear punch assay, was unchanged in PAK12/2 mice. Surprisingly, however, we observed a notable increase in PAK2 expression and phosphorylation in ischemic gastrocnemius tissue from PAK12/2 but not PAK1+/+ mice. Furthermore, we observed higher levels of activated ERK2, but not AKT, in ischemic and non-ischemic muscle of PAK12/2 mice upon hindlimb ischemic injury. A group I PAK inhibitor, IPA3, significantly inhibited endothelial cell sprouting from aortic rings in both PAK12/2 and PAK1+/+ mice, implying that PAK2 is a potential contributor to this process. Taken together, our data indicate that while PAK1 has the potential to contribute to neovascularization and wound healing, PAK2 may functionally compensate when PAK1 is deficient.

Original languageEnglish
Article number0112239
JournalPloS one
Volume9
Issue number11
DOIs
StatePublished - Nov 7 2014
Externally publishedYes

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    Elsherif, L., Ozler, M., Zayed, M. A., Shen, J. H., Chernoff, J., Faber, J. E., & Parise, L. V. (2014). Potential compensation among group I PAK members in hindlimb ischemia and wound healing. PloS one, 9(11), [0112239]. https://doi.org/10.1371/journal.pone.0112239