Tissue-Specific Roles of Transforming Growth Factor Beta Ligands in Cardiac Outflow Tract Malformations and Calcific Aortic Valve Disease
Date of Award
Open Access Dissertation
Congenital heart defects and adult calcific aortic valve disease are two of the leading causes of morbidity and mortality worldwide. To date, there is no medical cure and surgical intervention is the main option of treatment. The cardiac outflow tract is the major site for these abnormalities, which are triggered by genetic and/or environmental factors that alter development and/or homeostasis. Recently, significant roles of TGFβ signaling in development of cardiovascular disorders have become more evident in humans, however, the specific requirement of individual TGFβ ligands on the pathogenesis of OFT malformations and diseases remains elusive. In the present work, three studies are conducted to understand the role of Tgfb1 in calcific aortic valve diseases, the cell-type specific role of Tgfb2 in OFT malformations, and the role of Tgfb3 in OFT malformations and myocardial development.
Augmented TGFβ1 signaling is reported in human patients with calcific aortic valve disease, the major cause of valve replacement surgery in the United States. However, the role of TGFβ1 in CAVD pathogenesis has not been investigated in vivo. In the first study, we generated for the first time Tgfb1Tg; Peri- cre Tg mouse model with overexpression of bioactive TGFβ1 in valve interstitial cells (VICs) and we conduct a longitudinal follow-up study during embryonic and adult lives (E13.5-1 year). We were able to recapitulate human-like CAVD with
Tgfb1 hyperactivation signature spontaneously and without using dietary or pharmacological triggers. We found significant gender differences in CAVD progression with male mice tending to have a more severe form of the disease and development of bicuspid aortic valves, the most prevalent cardiovascular malformation in humans. Finally, we were able to attenuate disease progression, but not development, using pharmacological and genetic approaches. Collectively, our study implies that Tgfb1 signaling causes the onset and progression of CAVD in mice and interfering with its pathway as new targeted therapy is warranted.
Cardiac outflow tract malformations are the major and most critical types of congenital heart defects. Tgfb2 and Tgfb3 mutations have been reported in human patients with Loeys-Dietz syndrome and/or Arrhythmogenic Right Ventricular Dysplasia, however, their roles in the pathogeneses of these diseases remain unknown. In the second study, we used the novel Tgfb2 flox/flox mice and we deleted Tgfb2 from the endocardial, myocardial, and neural crest cells using tissue specific Cre mice. We found overlapping and distinct roles of Tgfb2 in OFT morphogenesis and we identified a novel finding that endocardial-produced Tgfb2 regulates OFT septation in a paracrine manner. In the third study, we generated and analyzed a large sample of Tgfb3 systemic knockouts embryos. We found that a significant number of mice develop cardiac valve remodeling defects and abnormal right ventricular myocardium but with incomplete penetrance. Overall, this work provides novel mechanisms which enhance our knowledge of the roles of TGFβ 1-3 ligands in OFT development and disease that could help in identifying targeted therapy or diagnostic biomarkers in the future.
Al-Sammarraie, N.(2019). Tissue-Specific Roles of Transforming Growth Factor Beta Ligands in Cardiac Outflow Tract Malformations and Calcific Aortic Valve Disease. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5539