p21Cip1 modulates arterial wound repair through the stromal cell–derived factor-1/CXCR4 axis in mice

Abstract

Cyclin-dependent kinase inhibitors, including p21 Cip1 , are implicated in cell turnover and are active players in cardiovascular wound repair. Here, we show that p21 Cip1 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 p21 Cip1 displayed accelerated proliferation of VSMCs and increased immune cell infiltration. BM transplantation experiments indicated that local p21 Cip1 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 p21 Cip1 inhibits STAT3 binding to the STAT-binding site within the murine SDF-1 promoter. Collectively, these results suggest that p21 Cip1 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.

A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice

“…It is also reported that DPP-4 cleaves multiple peptides, including stromal derived factor (SDF)-1 alpha, which is also known as C-X-C motif chemokine 12 (CXCL12), in addition to incretins 48) . There are reports showing that SDF-1 demonstrated protection against ischemic tissues and injured arteries 49,50) . In contrast, a recently published study demonstrated that neutralization of SDF-1 by antibody reduced intracranial aneurysm formation thorough suppression of angiogenesis and cell proliferation in the wall of aneurysms 51) , indicating that increased SDF-1 by inhibition of DPP-4 may compromise the beneficial effects of DPP-4I on AAA.…”

Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice

“…Inflammation, cytokine production, and VSMC proliferation are pivotal aspects of arterial wound repair (1,2). Unfortunately, this process often culminates in excessive neointimal formation and decreased luminal diameter (1,2), a pathology associated with adverse clinical outcomes (3).…”

“…Unfortunately, this process often culminates in excessive neointimal formation and decreased luminal diameter (1,2), a pathology associated with adverse clinical outcomes (3). Although early inflammation is known to modulate this process (4), given the clinical implications of reduced luminal diameter (3), investigators have generally chosen to focus on late events surrounding neointimal formation and VSMC proliferation.…”

“…An additional key component of this process is the recruitment of macrophages and T cells (1,2,5). While certain regulatory subtypes differ in their responses (6,7), macrophage and T cell recruitment typically leads to enhanced inflammation and neointimal formation as well as reduced luminal patency (1,2,5,(8)(9)(10)(11).…”

“…While certain regulatory subtypes differ in their responses (6,7), macrophage and T cell recruitment typically leads to enhanced inflammation and neointimal formation as well as reduced luminal patency (1,2,5,(8)(9)(10)(11). A complex network of cytokines, chemokines, and their receptors is known to regulate recruitment of these cells (2,5,(10)(11)(12)(13)(14).…”