Vascular Smooth Muscle Cell Apoptosis Promotes Transplant Arteriosclerosis Through Inducing the Production of SDF-1α

Abstract

Transplant arteriosclerosis is a leading cause of late allograft loss. Medial smooth muscle cell (SMC) apoptosis is considered to be an important event in transplant arteriosclerosis. However, the precise contribution of medial SMC apoptosis to transplant arteriosclerosis and the underlying mechanisms remain unclear. We transferred wild‐type p53 to induce apoptosis of cultured SMCs. We found that apoptosis induces the production of SDF‐1α from apoptotic and neighboring viable cells, resulting in increased SDF‐1α in the culture media. Conditioned media from Ltv‐p53‐transferred SMCs activated PI3K/Akt/mTOR and MAPK/Erk signaling in a SDF‐1α‐dependent manner and thereby promoted mesenchymal stem cell (MSC) migration and proliferation. In a rat aorta transplantation model, lentivirus‐mediated BclxL transfer selectively inhibits medial SMC apoptosis in aortic allografts, resulting in a remarkable decrease of SDF‐1α both in allograft media and in blood plasma, associated with diminished recruitment of CD90+CD105+ double‐positive cells and impaired neointimal formation. Systemic administration of rapamycin or PD98059 also attenuated MSC recruitment and neointimal formation in the aortic allografts. These results suggest that medial SMC apoptosis is critical for the development of transplant arteriosclerosis through inducing SDF‐1α production and that MSC recruitment represents a major component of vascular remodeling, constituting a relevant target and mechanism for therapeutic interventions.

Endothelial Cell Apoptosis Induces TGF-β Signaling-Dependent Host Endothelial–Mesenchymal Transition to Promote Transplant Arteriosclerosis

“…Nontransgenic or transgenic Enhanced green fluorescent protein (EGFP) Sprague–Dawley and Wistar rats were respectively served as syngenic and allogenic recipients. Abdominal aortic transplantation was performed as described by our previous study . For pharmaceutical treatment, SIS3 (5 mg/kg/day), AP23573 (2.0 mg/kg/day), or PD98059 (10 mg/kg/day) was administrated to allogenic recipients via intraperitoneal injection, respectively.…”

“…Recombinant lentiviral vectors carrying a specific Tie1 promoter and the downstream rat p53 (Ltv‐p53) fused to enhanced green fluorescent protein (EGFP) was constructed as described previously . ECs were incubated with Opti‐MEM I medium (Invitrogen, Carlsbad, CA) containing 200 multiplicity of infection (MOI) per cell of Ltv‐vector‐EGFP or Ltv‐p53‐EGFP in the presence of polybrene (5 µg/mL).…”

“…Indeed, to date, a number of studies have reported that the SMCs in the neointima in cases of TA are donor‐derived, especially derived from the migration and proliferation of the SMCs of the medial layer or progenitor cells from the adventitial layer of allograft arteries . In contrast, other studies reported that the injury response of the medial layer (such as SMC apoptosis) within allograft arteries could promote the host‐originating cells to participate in the formation of neointima in TA . Thus, a better understanding of the mechanism of the origin of neointimal SMCs could aid in the development of novel approaches to control TA and thereby improve the long‐term survival of transplanted organs.…”

Evolving Perspectives of mTOR Complexes in Immunity and Transplantation

“…For example, alloimmune injury in animal models induces medial smooth muscle cell damage, apoptosis as well as migration and proliferation of reparative BM-derived cells, processes that propagate neointimal formation and lumen occlusion (85,86). In a rat aorta transplantation model, systemic administration of RAPA attenuated these processes (85).…”

Pharmacological Inhibition of Vanin Activity Attenuates Transplant Vasculopathy in Rat Aortic Allografts

“…32,33 Inhibition of SMC apoptosis is known to break this vicious circle and to attenuate NI formation. 34 We could show that inhibition of vanin activity prevented TNF-α-induced SMC apoptosis in vitro.…”