Abstract
Background
Williams–Beuren syndrome (WS) is characterized by cardiovascular abnormalities associated with a multigene deletion on 7q11.23, in particular elastin (ELN). Peripheral pulmonary artery stenosis (PPAS) frequently affects pediatric patients with WS. Molecular investigation of WS pulmonary arterial (PA) tissue is limited by tissue scarcity.
Methods
We compared transcriptomes, tissue architecture, and localized changes in protein expression in PA tissue from patients with WS (n = 8) and donors (n = 5).
Results
Over 100 genes were differentially expressed at the ≥4-fold level, including genes related to the serotonin signaling pathway: >60-fold downregulation of serotonin transporter SLC6A4 and >3-fold upregulation of serotonin receptor HTR2A. Histologic examination revealed abnormal elastin distribution and smooth muscle cell morphology in WS PA, with markedly shorter, disorganized elastin fibers, and expanded proteoglycan-rich extracellular matrix between muscle layers.
Conclusions
There were significant abnormalities in the PA expression of genes regulating serotonin signaling, metabolism, and receptors in WS. Those changes were associated with distinct changes in the arterial structure and may play a role in the stenosis-promoting effects of elevated shear stress at PA bifurcations in WS.
Impact
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Serotonin pathway signaling is significantly altered in the pulmonary arteries of patients with Williams syndrome and severe peripheral arterial stenosis.
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The present study compares the histological and biochemical characteristics of pulmonary arteries from patients with Williams syndrome to those of controls, something that has not, to our knowledge, been done previously. It demonstrates marked abnormalities in the pulmonary arteries of patients with Williams syndrome, especially significant pathologic alterations in the signaling of the serotonin pathway.
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The findings of this study provide direction for the development of potential therapies to treat pulmonary artery stenosis in patients with Williams syndrome.
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References
Pober, B. R. Williams-Beuren syndrome. N. Engl. J. Med. 362, 239–252 (2010).
Adams, G. N. & Schmaier, A. H. The Williams-Beuren Syndrome-a window into genetic variants leading to the development of cardiovascular disease. PLoS Genet. 8, e1002479 (2012).
Angelov, S. N., Zhu, J., Hu, J. H. & Dichek, D. A. What’s the skinny on elastin deficiency and supravalvular aortic stenosis? Arterioscler. Thromb. Vasc. Biol. 37, 740–742 (2017).
Collins, R. T. 2nd, Kaplan, P., Somes, G. W. & Rome, J. J. Cardiovascular abnormalities, interventions, and long-term outcomes in infantile Williams syndrome. J. Pediatr. 156, 253–258.e251 (2010).
Collins, R. T. 2nd, Kaplan, P., Somes, G. W. & Rome, J. J. Long-term outcomes of patients with cardiovascular abnormalities and williams syndrome. Am. J. Cardiol. 105, 874–878 (2010).
Karimi, A. & Milewicz, D. M. Structure of the elastin-contractile units in the thoracic aorta and how genes that cause thoracic aortic aneurysms and dissections disrupt this structure. Can. J. Cardiol. 32, 26–34 (2016).
Li, D. Y. et al. Elastin is an essential determinant of arterial morphogenesis. Nature 393, 276–280 (1998).
Martin, E., Mainwaring, R. D., Collins, R. T. 2nd, MacMillen, K. L. & Hanley, F. L. Surgical repair of peripheral pulmonary artery stenosis in patients without Williams or Alagille syndromes. Semin. Thorac. Cardiovasc. Surg. 32, 973–979 (2020).
Jiao, Y. et al. Deficient circumferential growth is the primary determinant of aortic obstruction attributable to partial elastin deficiency. Arterioscler. Thromb. Vasc. Biol. 37, 930–941 (2017).
Li, D. Y. et al. Novel arterial pathology in mice and humans hemizygous for elastin. J. Clin. Investig. 102, 1783–1787 (1998).
Mochizuki, S., Brassart, B. & Hinek, A. Signaling pathways transduced through the elastin receptor facilitate proliferation of arterial smooth muscle cells. J. Biol. Chem. 277, 44854–44863 (2002).
Parrish, P. C. R. et al. Whole exome sequencing in patients with Williams-Beuren syndrome followed by disease modeling in mice points to four novel pathways that may modify stenosis risk. Hum. Mol. Genet. 29, 2035–2050 (2020).
Collins, R. T. 2nd Cardiovascular disease in Williams syndrome. Circulation 127, 2125–2134 (2013).
Monge, M. C. et al. Surgical reconstruction of peripheral pulmonary artery stenosis in Williams and Alagille syndromes. J. Thorac. Cardiovasc. Surg. 145, 476–481 (2013).
Ma, X. et al. Tetralogy of Fallot: aorto-pulmonary collaterals and pulmonary arteries have distinctly different transcriptomes. Pediatr. Res. 76, 341–346 (2014).
Shen, Y. H., Lu, H. S., LeMaire, S. A. & Daugherty, A. Unfolding the story of proteoglycan accumulation in thoracic aortic aneurysm and dissection. Arterioscler. Thromb. Vasc. Biol. 39, 1899–1901 (2019).
Milewicz, D. M. et al. Altered smooth muscle cell force generation as a driver of thoracic aortic aneurysms and dissections. Arterioscler. Thromb. Vasc. Biol. 37, 26–34 (2017).
Ingber, D. E. Tensegrity-based mechanosensing from macro to micro. Prog. Biophys. Mol. Biol. 97, 163–179 (2008).
Wang, N., Tytell, J. D. & Ingber, D. E. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat. Rev. Mol. Cell Biol. 10, 75–82 (2009).
Roccabianca, S., Bellini, C. & Humphrey, J. D. Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology. J. R. Soc. Interface 11, 20140397 (2014).
Humphrey, J. D., Milewicz, D. M., Tellides, G. & Schwartz, M. A. Cell biology. Dysfunctional mechanosensing aneuryms. Science. 344, 477–479 (2014).
Pena-Silva, R. A., Miller, J. D., Chu, Y. & Heistad, D. D. Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves. Am. J. Physiol. Heart Circ. Physiol. 297, H1354–H1360 (2009).
Akhtar, K. et al. Oxidative and nitrosative modifications of tropoelastin prevent elastic fiber assembly in vitro. J. Biol. Chem. 285, 37396–37404 (2010).
Acknowledgements
These studies were supported by the congenital division of the department of Cardiothoracic Surgery.
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Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: all authors. Drafting the article or revising it critically for important intellectual content: X.M., R.T.C., A.G., and R.K.R. Final approval of the version to be published: X.M., R.T.C., and R.K.R.
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Human specimen collection was conducted under a Stanford University-approved expedited IRB protocol in which patient consent was not required.
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Ma, X., Collins, R.T., Goodman, A. et al. Pulmonary arteries of Williams syndrome patients exhibit altered serotonin metabolism genes and degenerated medial layer architecture. Pediatr Res 90, 1065–1072 (2021). https://doi.org/10.1038/s41390-020-01359-5
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DOI: https://doi.org/10.1038/s41390-020-01359-5
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