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Murine Marfan Syndrome Sildenafil Treatment

ABSTRACT: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene. While aortic rupture is the major cause of mortality in MFS, patients also suffer from poorly understood pulmonary complications. Loss of basal nitric oxide (NO) production and vascular integrity are proposed to take part in MFS aortic root disease, yet their contribution to lung complications has yet to be determined. Due to its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 (PDE5) inhibitor sildenafil (SIL) could attenuate aortic root remodelling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation and exacerbated elastic fibrefiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent micro-array analyses showed changes to gene signatures involved in the inflammatory response in MFS lung treated with SIL, without significant downregulation of connective tissue or TGF-β signalling genes. Since PDE5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodelling.

ORGANISM(S): Mus musculus

PROVIDER: GSE128481 | GEO | 2019/03/19

REPOSITORIES: GEO

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Project description:Located at the junction of left ventricle and ascending aorta, aortic root is a central cardiovascular structure consisting of aortic valve and coronary ostium that are essential for systemic and coronary circulation, respectively. Malformations of aortic valve and coronary ostium are common birth defects and may occur together in human patients, leading to complex complications including aortic valve stenosis, myocardial ischemia, heart failure and sudden cardiac death. Despite of their physiological and clinical significances, the developmental and molecular mechanisms by which coordinate the formation of aortic valve and coronary ostium remain poorly understood. Here we report that SOX17 (SRY-box 17) is an essential transcription factor required for the maturation of aortic root, as well as the patterning of aortic valve and coronary ostium. We show in mouse that deletion of Sox17 in the aortic root endothelium results in defective aortic valve with underdeveloped non-coronary leaflet (NCL) or bicuspid aortic valve (BAV) without NCL. The valve defects are accompanied by misplaced left coronary ostium that reduces coronary blood flow, leading to myocardial hypoxia and death of embryos. Mechanistically, deletion of Sox17 decreases the expression of Pdgfb (Platelet derived growth factor, B polypeptide) in the aortic root endothelium and the PDGF growth signaling in the NCL mesenchyme and aortic root smooth muscle, both of which are derived from the second heart field (SHF) cardiomyocyte precursors. Furthermore, the deletion upregulates the expression of Ctgf (Connective tissue growth factor) and the extracellular matrix (ECM) genes, whereas downregulates the vascular smooth muscle genes, in the forming aortic root. Together, these findings support a developmental disease mechanism in which delayed growth and maturation of aortic root, due to lack of SOX17-PDGF/CTGF signaling, contributes to BAV and CAAs, two common congenital cardiovascular defects.

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Murine Marfan Syndrome Sildenafil Treatment

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