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A Method for Labeling Vasculature in Embryonic Mice
Published on: October 7, 2011
KIS protects against adverse vascular remodeling by opposing stathmin-mediated VSMC migration in mice
Thomas H Langenickel1, Michelle Olive, Manfred Boehm
1Vascular Biology and Genomics Section, Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Abstract:
Vascular proliferative diseases are characterized by VSMC proliferation and migration. Kinase interacting with stathmin (KIS) targets 2 key regulators of cell proliferation and migration, the cyclin-dependent kinase inhibitor p27Kip1 and the microtubule-destabilizing protein stathmin. Phosphorylation of p27Kip1 by KIS leads to cell-cycle progression, whereas the target sequence and the physiological relevance of KIS-mediated stathmin phosphorylation in VSMCs are unknown. Here we demonstrated that vascular wound repair in KIS-/- mice resulted in accelerated formation of neointima, which is composed predominantly of VSMCs. Deletion of KIS increased VSMC migratory activity and cytoplasmic tubulin destabilizing activity, but abolished VSMC proliferation through the delayed nuclear export and degradation of p27Kip1. This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of KIS-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation. Downregulation of stathmin in KIS-/- VSMCs fully restored the phenotype, and stathmin-deficient mice demonstrated reduced lesion formation in response to vascular injury. These data suggest that KIS protects against excessive neointima formation by opposing stathmin-mediated VSMC migration and that VSMC migration represents a major mechanism of vascular wound repair, constituting a relevant target and mechanism for therapeutic interventions.
Insights
Kinase interacting with stathmin (KIS) deficiency accelerates vascular wound repair by increasing smooth muscle cell migration via stathmin. This highlights stathmin as a therapeutic target for preventing excessive neointima formation.
Area of Science:
- Vascular biology
- Cellular signaling
- Molecular mechanisms of disease
Background:
- Vascular proliferative diseases involve smooth muscle cell (VSMC) proliferation and migration.
- Kinase interacting with stathmin (KIS) regulates cell proliferation and migration by targeting p27Kip1 and stathmin.
- The role of KIS-mediated stathmin phosphorylation in VSMCs is not fully understood.
Purpose of the Study:
- To investigate the physiological relevance of KIS-mediated stathmin phosphorylation in vascular wound repair.
- To elucidate the role of KIS in regulating VSMC behavior and neointima formation.
Main Methods:
- Utilized KIS knockout (KIS-/-) mice to study vascular wound repair.
- Assessed VSMC proliferation, migration, and tubulin destabilizing activity.
- Analyzed protein levels and phosphorylation status of p27Kip1 and stathmin.
- Investigated the effect of stathmin downregulation in KIS-/- VSMCs and stathmin-deficient mice.
Main Results:
- KIS deficiency led to accelerated neointima formation, increased VSMC migration, and enhanced tubulin destabilization.
- Loss of KIS abolished VSMC proliferation due to delayed p27Kip1 nuclear export and degradation.
- Increased stathmin levels in KIS-/- VSMCs resulted from impaired KIS-mediated phosphorylation and degradation.
- Stathmin downregulation restored normal phenotype in KIS-/- VSMCs, and stathmin-deficient mice showed reduced lesion formation.
Conclusions:
- KIS protects against excessive neointima formation by inhibiting stathmin-mediated VSMC migration.
- VSMC migration is a critical mechanism in vascular wound repair.
- Stathmin represents a potential therapeutic target for vascular proliferative diseases.
