Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS individuals, although the reason for such vulnerability remains poorly understood. In this work, we develop a microfluidic chip formed by HGPS-SMCs generated from induced pluripotent stem cells (iPSCs), to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detach from the chip after a few days of culture; this process is mediated by the upregulation of metalloprotease 13 (MMP13). Importantly, double-mutant Lmna G609G/G609G Mmp13 −/− mice or Lmna G609G/G609G Mmp13 +/+ mice treated with a MMP inhibitor show lower SMC loss in the aortic arch than controls. MMP13 upregulation appears to be mediated, at least in part, by the upregulation of glycocalyx. Our HGPS-SMCs chip represents a platform for developing treatments for HGPS individuals that may complement previous pre-clinical and clinical treatments.

Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome

“…The severity of the arterial disease depends on levels of progerin expression; the arterial pathology is more severe — and the onset is earlier — in mice that have 2 targeted HGPS mutant alleles as compared with only 1 ( 12 , 13 ). The arterial disease is less severe in HGPS mice treated with a farnesyltransferase inhibitor ( 14 ), an antisense oligonucleotide that alters RNA splicing and reduces progerin expression ( 11 ), or by inhibiting N-acetyltransferase 10 ( 15 ), endoplasmic reticulum stress ( 16 ), MMP13 ( 17 ), or ICMT ( 18 ).…”

Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson‐Gilford Progeria syndrome

“…Since SM2a‐Cre‐mediated VSMC‐specific expression of progerin is sufficient to accelerate pathologic vascular alterations and death in atheroprone Apolipoprotein E‐null mice (Hamczyk et al, 2018 ), progerin‐induced vascular pathology may be directly related to the cause of death in patients. Although the precise mechanism(s) underlying the vascular changes remains to be clarified, HGPS VSMCs and endothelial cells are more sensitive to mechanical stress, have been shown to be particularly susceptible to progerin accumulation and are exposed to the higher hemodynamic forces (pressure and shear stress) exerted on arterial walls (Varga et al, 2006 ; Verstraeten et al, 2008 ), which may be influenced by dysregulation of the glycocalyx components involved in flow shear stress sensing (Pitrez et al, 2020 ). Progerin‐induced VSMC vulnerability has also been attributed to dysregulation of the DNA damage response pathway, hyperactivation of ER stress (ER), and the unfolded protein response (UPR) (Hamczyk et al, 2019 ; Kinoshita et al, 2017 ; Zhang et al, 2014 ).…”

Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

“…Additional genetic and pharmacological strategies have proved successful in reducing or preventing VSMC loss in HGPS-like mice. These strategies include deletion of the matrix metalloprotease 13 ( Mmp13 ) gene, the use of the matrix metalloprotease inhibitor batimastat [ 94 ], and the blockade of interleukin-6 signaling with the neutralizing antibody tocilizumab [ 95 ] in Lmna G609G/G609G mice, suggesting that HGPS-associated VSMC depletion involves ECM remodeling and inflammation. VSMC loss in Lmna G609G/G609G mice was also prevented by inhibition of N-acetyltransferase 10 with remodelin, and this treatment also ameliorated aortic adventitial thickening and extended lifespan [ 96 ].…”