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

Laila Elsherif1, Mehmet Ozler1, Mohamed A Zayed1

  • 1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.

Plos One
|November 8, 2014
PubMed

Insights

While PAK1 deficiency showed minimal impact on neovascularization and wound healing, PAK2 compensated, suggesting its crucial role in these processes when PAK1 is absent.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Physiology

Background:

  • p21-activated kinases (PAKs) are serine/threonine kinases regulating cytoskeletal dynamics and cell migration.
  • PAK1 activation involves binding to CIB1 or Rho GTPases like Rac1 and Cdc42.
  • PAK1's role in angiogenesis has been primarily studied in vitro, with its in vivo function in neovascularization and wound healing unexamined.

Purpose of the Study:

  • To investigate the in vivo role of PAK1 in ischemic neovascularization and wound healing using a global PAK1 knockout mouse model.
  • To determine if PAK1 is essential for arteriogenesis and angiogenesis following hindlimb ischemia.
  • To assess the impact of PAK1 deficiency on wound healing rates.

Main Methods:

  • Utilized a global PAK1 knockout mouse model (PAK1-/-) and wild-type littermates (PAK1+/+).
  • Assessed neovascularization via unilateral hindlimb ischemia, monitoring plantar perfusion, limb use, and appearance over 21 days.
  • Evaluated wound healing using an ear punch assay and analyzed protein expression (PAK2, ERK2, AKT) and phosphorylation in muscle tissue.

Main Results:

  • PAK1 knockout mice showed no significant difference in neovascularization compared to wild-type mice, although a slight delay in healing was observed in older knockout mice.
  • Wound healing rates were unchanged in PAK1 knockout mice.
  • Increased PAK2 expression and phosphorylation, along with elevated activated ERK2, were observed in ischemic muscle of PAK1 knockout mice.
  • In vitro, a PAK inhibitor (IPA3) inhibited endothelial cell sprouting in both PAK1-/- and PAK1+/+ mice, suggesting PAK2 involvement.

Conclusions:

  • PAK1 is not essential for ischemic neovascularization or wound healing in vivo, as PAK2 can functionally compensate for its absence.
  • PAK2 plays a significant role in endothelial cell sprouting and may contribute to neovascularization processes.
  • The study highlights the potential for functional redundancy between PAK family members in vascular repair mechanisms.

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