Potential compensation among group I PAK members in hindlimb ischemia and wound healing.
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 hypothesis 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 PAK1-/- and PAK1+/+ mice throughout the 21-day period following hindlimb ischemia; however a slightly delayed healing was observed in 16 week old PAK1-/- mice. In addition, the wound healing rate, as assessed with an ear punch assay, was unchanged in PAK1-/- mice. Surprisingly, however, we observed a notable increase in PAK2 expression and phosphorylation in ischemic gastrocnemius tissue from PAK1-/- but not PAK1+/+ mice. Furthermore, we observed higher levels of activated ERK2, but not AKT, in ischemic and non-ischemic muscle of PAK1-/- mice upon hindlimb ischemic injury. A group I PAK inhibitor, IPA3, significantly inhibited endothelial cell sprouting from aortic rings in both PAK1-/- 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.
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
Laila
L
Elsherif
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
Mehmet
M
Ozler
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
Mohamed A
MA
Zayed
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
Jessica H
JH
Shen
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America.
Jonathan
J
Chernoff
Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America; McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
James E
JE
Faber
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America; McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
Leslie V
LV
Parise
D000818:Animals; D002465:Cell Movement; D005260:Female; D017353:Gene Deletion; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D014945:Wound Healing; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
C515905:Pak1 protein, mouse; C515909:Pak2 protein, mouse; D054462:p21-Activated Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3