The role of Bcl11b in vascular smooth muscle cell death

Abstract

Arterial stiffening is a strong independent risk factor for cardiovascular disease. B-cell leukaemia 11b (BCL11B) is a transcription factor known as an essential regulator in T lymphocytes differentiation and neuronal development. Several genome-wide association studies showed that single nucleotide polymorphisms (SNPs) in the 3’gene desert of Bcl11b are associated with a higher susceptibility for aortic stiffness and blood pressure control. However, its role in smooth muscle cells and mechanism of action remains to be uncovered. Our aims are: (1) to analyse the role of Bcl11b in vascular system; (2) to characterize the signalling pathways related to Bcl11b in cell death. Morphological, cellular and molecular analysis were carried out on the arteries of smooth muscle cell-specific Bcl11b-knockout mice at 3, 7, 28 days after tamoxifen injections as well as on the smooth muscle cells isolated from the aorta of Bcl11b-floxed mice that were cultured and inactivated by Cre recombinase using adenoviral vectors. We analysed mice with Bcl11b deletion in vascular SMC (Bcl11b-SMKO). There is no difference between control and mutant mice at the macroscopic level 3 days after Bcl11b KO induction, however, 7 days after Bcl11b inactivation, 70% of the Bcl11b-SMKO mice showed signs of haemorrhage in the distal part of the thoracic aorta near the abdominal aorta. The histological examination of thoracic aorta at day 7 indicated the presence of “bumpy region” in the mutant aorta, these areas seem to be covered by a thicker layer of extracellular matrix and the presence of IgG positive cells, indicating that cell death via necroptosis is occurring in this tissue. Our preliminary results from smooth muscle cell culture indicate higher cell death rate in the mutant cells compared to control cells. Our data suggest a primary effect of Bcl11b inactivation on cell death, probably through necroptosis. The mechanisms linked to cell death induced by Bcl11b loss is under investigation.