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Published on: April 1, 2015
p21Cip1 modulates arterial wound repair through the stromal cell-derived factor-1/CXCR4 axis in mice
Michelle Olive1, Jason A Mellad, Leilani E Beltran
1Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20817, USA.
Abstract:
Cyclin-dependent kinase inhibitors, including p21Cip1, are implicated in cell turnover and are active players in cardiovascular wound repair. Here, we show that p21Cip1 orchestrates the complex interactions between local vascular and circulating immune cells during vascular wound repair. In response to femoral artery mechanical injury, mice with homozygous deletion of p21Cip1 displayed accelerated proliferation of VSMCs and increased immune cell infiltration. BM transplantation experiments indicated that local p21Cip1 plays a pivotal role in restraining excessive proliferation during vascular wound repair. Increased local vascular stromal cell-derived factor-1 (SDF-1) levels were observed after femoral artery injury in p21+/+ and p21-/- mice, although this was significantly greater in p21-/- animals. In addition, disruption of SDF-1/CXCR4 signaling inhibited the proliferative response during vascular remodeling in both p21+/+ and p21-/- mice. We provide evidence that the JAK/STAT signaling pathway is an important regulator of vascular SDF-1 levels and that p21Cip1 inhibits STAT3 binding to the STAT-binding site within the murine SDF-1 promoter. Collectively, these results suggest that p21Cip1 activity is essential for the regulation of cell proliferation and inflammation after arterial injury in local vascular cells and that the SDF-1/CXCR4 signaling system is a key mediator of vascular proliferation in response to injury.
Insights
The cyclin-dependent kinase inhibitor p21Cip1 regulates vascular wound repair by controlling cell proliferation and immune cell infiltration. It restrains excessive smooth muscle cell growth and inflammation following arterial injury.
Area of Science:
- Cardiovascular Biology
- Cellular Regulation
- Immunology
Background:
- Cyclin-dependent kinase inhibitors (CKIs), such as p21Cip1, are crucial for cell cycle control.
- These molecules play significant roles in tissue repair processes, particularly in the cardiovascular system.
- Understanding the precise mechanisms of CKIs in vascular wound healing is essential for therapeutic development.
Purpose of the Study:
- To elucidate the role of p21Cip1 in orchestrating cellular and immune responses during vascular wound repair.
- To investigate the impact of p21Cip1 deficiency on vascular smooth muscle cell (VSMC) proliferation and immune cell infiltration after injury.
- To determine the involvement of stromal cell-derived factor-1 (SDF-1)/CXCR4 and JAK/STAT signaling pathways in p21Cip1-mediated vascular repair.
Main Methods:
- Utilized a mouse model with homozygous deletion of p21Cip1 (p21-/-) subjected to femoral artery mechanical injury.
- Conducted bone marrow (BM) transplantation experiments to assess the role of local p21Cip1.
- Measured vascular stromal cell-derived factor-1 (SDF-1) levels and analyzed the effects of disrupting SDF-1/CXCR4 signaling.
- Investigated the JAK/STAT signaling pathway and its interaction with p21Cip1 and the SDF-1 promoter.
Main Results:
- p21Cip1 deficiency led to accelerated VSMC proliferation and increased immune cell infiltration after femoral artery injury.
- Local p21Cip1 was found to be critical in restraining excessive proliferation during vascular wound repair.
- Elevated SDF-1 levels were observed in p21-/- mice, and SDF-1/CXCR4 signaling disruption inhibited proliferation in both p21+/+ and p21-/- mice.
- The JAK/STAT pathway regulates vascular SDF-1 levels, with p21Cip1 inhibiting STAT3 binding to the SDF-1 promoter.
Conclusions:
- p21Cip1 is essential for regulating cell proliferation and inflammation in local vascular cells following arterial injury.
- The SDF-1/CXCR4 signaling system acts as a key mediator of vascular proliferation in response to injury.
- p21Cip1 plays a pivotal role in controlling the complex cellular crosstalk during cardiovascular wound repair.
