Regulation of PDE5 expression in human aorta and thoracic aortic aneurysms

Valeriana Cesarini,Giorgio Antonelli,Calogera Pisano,Giovanni Ruvolo,Flavia Botti,Gabriele Rossi,Carmela Rita Balistreri,Susanna Dolci,Emmanuele A Jannini

doi:10.1038/s41598-019-48432-6

Valeriana Cesarini, Giorgio Antonelli + Show 7 more

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https://doi.org/10.1038/s41598-019-48432-6

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Aneurysms and dissections affecting thoracic aorta are associated with smooth muscle cell (SMC) dysfunction. NO/cGMP signaling pathway in smooth muscle cells has been shown to be affected in sporadic thoracic aortic aneurysms. We analyzed the mRNA levels of PDE5, a cGMP-hydrolyzing enzyme highly expressed in aortic SMCs, that regulates arterious vascular tone by lowering cGMP levels. We found that aortic tissue obtained from Marfan, tricuspid and bicuspid thoracic aneurysms expressed lower levels of PDE5 mRNA compared to control aortas. In particular, we found that affected aortas showed lower levels of all the PDE5A isoforms, compared to control aortas. Transfection of vascular SMCs (VSMCs) with NOTCH3 activated domain (NICD3) induced the expression of PDE5A1 and A3 protein isoforms, but not that of the corresponding mRNAs. VSMC stimulation with GSNO, a nitric oxide analogue or with 8-br-cGMP, but not with 8-br-cAMP, up-regulated PDE5 and NOTCH-3 protein levels, indicating a negative feedback loop to protect the arterial wall from excessive relaxation. Finally, we found that PDE5 is expressed early during human aorta development, suggesting that if loss of function mutations of PDE5 occur, they might potentially affect aortic wall development.

Highlights

Thoracic aortic aneurysm (TAA) and dissection (TAD) remain a significant clinical challenge due to their high morbidity and mortality[1,2]
Since we found that NOTCH1 and NOTCH3 levels are differentially expressed in the aortic aneurysm samples, we evaluated if they might regulate PDE5 expression in vascular SMCs (VSMCs) in vitro
Genetic alterations of factors that regulate the nitric oxide (NO)/cGMP pathway have been shown to occur in a subset of familiar thoracic aortic aneurysms, indicating that unbalanced cGMP-dependent cascade plays an important role in the generation of aortic wall defects

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Introduction

Thoracic aortic aneurysm (TAA) and dissection (TAD) remain a significant clinical challenge due to their high morbidity and mortality[1,2]. Recent studies showed a genetic basis of all forms of TAA even in the sporadic type[7] It is predominantly inherited in an autosomal dominant fashion with reduced penetrance and variable expression, showing significant genetic (>20 gene) and clinical (location, severity and age onset) heterogeneity[8]. PDE5 is highly expressed in smooth muscle cells of vessels and as for other PDEs, three isoforms have been identified in humans including PDE5A1, PDE5A2, and PDE5A330–32. Considering the role of PDE5 in regulating the level of cGMP in smooth muscle cells, in this pilot study we sought to analyse PDE5, NOTCH1 and NOTCH3 expression in TAA patients with Marfan’s Syndrome, BAV and TAV. To understand if PDE5 can play a role in aorta development, we studied its ontogenetic expression profile during early fetal development, both in mice and humans

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