ALK1/ACVRL1 overexpression in human non-atheromasic ascending thoracic aortic aneurysms and atherosclerotic lesions.

Ascending Thoracic Aortic Aneurysms (ATAA) is a devastating disease, consisting in dilatation of ascending aorta, often resulting in aortic wall dissection. In spite of its heterogeneous aetiology, histologic ATAA features invariably involve marked extracellular matrix (ECM) fragmentation, vascular smooth muscle cell (VSMC) necrosis, cystic degeneration. ATAA seems to arise from a disrupted ECM depostion/degradation homeostasis, abnormally imbalanced towards demolition. Although the complex cellular/molecular ATAA-determining mechanisms are still poorly understood, several studies suggest a key role played by Transforming-Growth–Factor-ß/Bone-Morphogenetic-Protein (TGFß/BMP) superfamily cytokines in ATAA pathogenesis. Many mendelian syndromes including ATAA in their clinical spectrum are caused by mutations in TGFß/BMP-signalling-cascade coding genes, such as TGFBR2, ACVRL5/TGFBR1, MADH3. Furthermore, impaired TGFß/BMP signalling has been described in both syndromic and non-syndromic ATAA samples [2]. Several authors have proposed that ATAA aortic wall cells display an altered TGFß/BMP receptorial reservoir, responsible for impaired TGFß/BMP responsiveness, similarly to pathogenic mechanisms already described for atherosclerosis [3-5] ALK1/ACVRL1 and Endoglin (ENG) are components of the signalling pathway of at least three members of TGFß/BMP superfamily, namely BMP9, TGFß-1 and TGFß-3. Moreover, ALK1/ACVRL1 and ENG genes are mutated in the vascular mendelian syndrome Hereditary Haemorrhagic Telangiectasia (HHT). Despite the well-known pivotal role of the two genes in vascular homeostasis, their involvement in ATAA has never been investigated.