Biology subjects

Escopete, S.

Publications and source records attributed to Escopete, S..

2 recordsLinked to original sources

bioRxiv2024

Identification of Disease-relevant, Sex-based Proteomic Differences in iPSC-derived Vascular Smooth Muscle

The prevalence of cardiovascular disease varies with sex, and the impact of intrinsic sex-based differences on vasculature is not well understood. Animal models can provide important insight into some aspects of human biology, however not all discoveries in animal systems translate well to humans. To explore the impact of chromosomal sex on proteomic phenotypes, we used iPSC-derived vascular smooth muscle cells from healthy donors of both sexes to identify sex-based proteomic differences and their possible effects on cardiovascular pathophysiology. Our analysis confirmed that differentiated cells have a proteomic profile more similar to healthy primary aortic smooth muscle than iPSCs. We also identified sex-based differences in iPSC- derived vascular smooth muscle in pathways related to ATP binding, glycogen metabolic process, and cadherin binding as well as multiple proteins relevant to cardiovascular pathophysiology and disease. Additionally, we explored the role of autosomal and sex chromosomes in protein regulation, identifying that proteins on autosomal chromosomes also show sex-based regulation that may affect the protein expression of proteins from autosomal chromosomes. This work supports the biological relevance of iPSC-derived vascular smooth muscle cells as a model for disease, and further exploration of the pathways identified here can lead to the discovery of sex-specific pharmacological targets for cardiovascular disease. SignificanceIn this work, we have differentiated 4 male and 4 female iPSC lines into vascular smooth muscle cells, giving us the ability to identify statistically-significant sex-specific proteomic markers that are relevant to cardiovascular disease risk (such as PCK2, MTOR, IGFBP2, PTGR2, and SULTE1).

molecular biology↗

bioRxiv2023

17 β-estradiol impedes aortic root dilation and rupture in male Marfan mice

Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with dilation of the aortic root. Human and animal models suggest a worse phenotype for males compared to females with respect to aneurysm size and risk of dissection. In this study we examine the effects of 17 {beta}-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 {beta}-estradiol and the growth in aortic root size along with the risk of aortic rupture or dissection with the addition of angiotensin II was measured. Transcriptomic profiling was used to identify enriched pathways from 17 {beta}-estradiol treatment. Aortic smooth muscle cells were then treated with cytokines in order to validate the mechanism of 17 {beta}-estradiol protection. We show that 17 {beta}-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture and dissection after treatment with angiotensin II. The Marfan transcriptome was enriched in inflammatory genes and the addition of 17 {beta}-estradiol modulated a set of genes that function through TNF mediated NF-{kappa}B signaling. These included many proteins known to play a role in the phenotypic shift of aortic smooth muscle cells from a contractile to a more inflammatory-like state such as Vcam-1, Mcp-1, Lgals3, Il-6, Il-1b, and C3. In addition, 17 {beta}-estradiol suppressed the induction of these TNF induced genes in aortic smooth muscle cells in vitro and this effect appears to be NF-{kappa}B dependent. In conclusion, 17 {beta}-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNF -NF-{kappa}B signaling and thus prevents the phenotypic switch of aortic smooth muscle cells from a contractile to an inflammatory state.

genetics↗