Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

Abstract

Thoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-β (TGF-β) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and β-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-β signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and β-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

“…In turn, the remodeled ECM can modify the gradients, bioavailability, and proteolytic activation of matrix-bound ligands [114,115]. Reviewing the vast number of signaling molecules that modulate VSMC's function goes beyond the scope of this review; however, we will briefly summarize the main features of three pathways that have been specifically implicated in TAA pathogenesis: angiotensin II, TGF-β, and Notch signaling [116,117].…”

“…AT 1 R also potentiates TGF-β signaling by inducing the expression of metalloproteinase-2 and -9 (MMP-2 and MMP-9), which are proteolytic enzymes that can catalyze the conversion of inactive ECM-bound latent TGF-β into its bioactive form [134][135][136]. AT 1 R signaling, which can be triggered through mechanical stretch, independently of angiotensin II [137][138][139][140], has been shown to be overactivated in mouse models of TAA by several mechanisms [117]. These include the upregulation of Agtr1a (the gene that in rodents codes for the major form of AT 1 R expressed in the thoracic aorta) via the ROS-dependent activation of nuclear factor kappa B (NF-kB); the de-repression of Agtr1a expression as a consequence of defective TGF-β signaling; and increased expression of angiotensin-converting enzyme, which is a positive regulator of the pathway [141][142][143].…”

“…TGF-β signaling regulates many aspects of VSMC biology, including positive regulation of VSMC-specific transcripts such as Myh11, Acta2, and Cnn1 (coding for SM-MHC, αSMA, and Calponin-1, respectively) [156][157][158]. Positive effectors of TGF-β signaling and TGF-β-responsive genes are upregulated in aneurysmal lesions of various etiology in both patients and mouse models, where they contribute to both adaptive and maladaptive responses [65,117,[159][160][161][162]. TGF-β signaling also closely interacts with other pathways that regulate VSMC phenotypes, including AT 1 R and Notch signaling [54,163].…”

“…Bicuspid aortic valve (BAV) is a common congenital defect that can be present in isolation or in association with other syndromic manifestations, and which associates with an increased risk of aortic aneurysm, frequently affecting the ascending aorta [2,6,117,333]. Although the genetic architecture of BAV is complex, increased risk for BAV is generally inherited in an autosomal-dominant manner, with variable expressivity and incomplete penetrance [334].…”

“…In contrast with direct TGF-β antagonism, treatment with antagonists of AT 1 R signaling, such as the angiotensin receptor blocker (ARB) losartan, invariably prevents the development of aneurysm in animal models; this beneficial effect associates with reduced levels of TGFβ ligand, pSmad2/3, and the expression of TGF-β target genes [117,143,159,313,[434][435][436]. In addition, the deletion of Agtr1a (gene encoding AT 1 R in mice) prevents aortic root dilation in two different MFS mouse models [437,438].…”