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Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+/- mice
Jiumei Cao1, Limin Gong, Dong-chuan Guo
1Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Abstract:
Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of SMC contractile proteins compared with WT SMCs. An inhibitor of mTOR signaling, rapamycin, decreased SMC proliferation and increased contractile protein expression in the Tsc2(+/-) SMCs to levels similar to WT SMCs. Exposure to alpha-elastin fragments also decreased proliferation of Tsc2(+/-) SMCs and increased levels of p27(kip1), but failed to increase expression of contractile proteins. In response to artery injury using a carotid artery ligation model, Tsc2(+/-) mice significantly increased neointima formation compared with the control mice, and the neointima formation was inhibited by treatment with rapamycin. These results demonstrate that Tsc2 haploinsufficiency in SMCs increases proliferation and decreases contractile protein expression and suggest that the increased proliferative potential of the mutant cells may be suppressed in vivo by interaction with elastin. These findings provide insights into the molecular pathogenesis of aortic disease in TSC patients and identify a potential therapeutic target for treatment of this complication of the disease.
Insights
Tuberous sclerosis complex (TSC) aortic aneurysms stem from Tsc2 mutations causing smooth muscle cell overgrowth. Rapamycin, an mTOR inhibitor, effectively reduced this proliferation, offering a potential therapeutic target for TSC-related aortic disease.
Area of Science:
- Vascular Biology
- Genetics
- Cell Biology
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder linked to TSC1 or TSC2 mutations.
- Aortic aneurysms, characterized by smooth muscle cell (SMC) proliferation, are a less-studied TSC complication.
- The role of TSC2 mutations in aortic aneurysm pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the pathogenesis of aortic aneurysms in Tuberous Sclerosis Complex (TSC) caused by TSC2 mutations.
- To explore the cellular mechanisms underlying smooth muscle cell (SMC) behavior in Tsc2(+/-) mice.
- To identify potential therapeutic targets for TSC-associated aortic disease.
Main Methods:
- Explantation and culture of smooth muscle cells (SMCs) from Tsc2(+/-) and wild-type (WT) mice.
- Analysis of mTOR signaling pathway components (mTOR, S6, p70S6K) and SMC contractile proteins.
- Treatment with rapamycin (mTOR inhibitor) and alpha-elastin fragments.
- Assessment of neointima formation in a carotid artery ligation model in Tsc2(+/-) mice.
Main Results:
- Tsc2(+/-) SMCs exhibited increased mTOR signaling, elevated proliferation, and reduced contractile protein expression compared to WT SMCs.
- Rapamycin treatment normalized SMC proliferation and contractile protein levels in Tsc2(+/-) cells.
- Alpha-elastin fragments reduced Tsc2(+/-) SMC proliferation but did not restore contractile protein expression.
- Tsc2(+/-) mice showed increased neointima formation after artery injury, which was inhibited by rapamycin.
Conclusions:
- Tsc2 haploinsufficiency in SMCs drives increased proliferation and decreased contractility, contributing to aortic disease in TSC.
- mTOR signaling inhibition via rapamycin shows therapeutic potential for TSC-related aortic aneurysms.
- Elastin interaction may modulate, but not fully correct, the cellular defects in Tsc2-deficient SMCs.
