Conundrum of angiotensin II and TGF-β interactions in aortic aneurysms

https://doi.org/10.1016/j.coph.2013.01.002Get rights and content

Angiotensin II (AngII) has been invoked as a principal mediator for the development and progression of both thoracic and abdominal aortic aneurysms. While there is consistency in experimental and clinical studies that overactivation of the renin angiotensin system promotes aortic aneurysm development, there are many unknowns regarding the mechanistic basis underlying AngII-induced aneurysms. Interactions of AngII with TGF-β in both thoracic and abdominal aortic aneurysms have been the focus of recent studies. While these studies have demonstrated profound effects of manipulating TGF-β activity on AngII-induced aortic aneurysms, they have also led to more questions regarding the interactions between AngII and this multifunctional cytokine. This review compiled the recent literature to provide insights into understanding the potentially complex interactions between AngII and TGF-β in the development of aortic aneurysms.

Highlights

► The renin angiotensin system plays a critical role on aortic aneurysmal formation and development. ► Angiotensin II and TGF-β have potential interactions in the development of aortic aneurysms. ► The definitive roles of TGF-β in the development of aortic aneurysms need to be clarified.

Section snippets

Overview of aortic aneurysms

Aortic aneurysms are a group of pathologies that have the common feature of permanent dilation, which occur in the thoracic (TAAs) and abdominal (AAAs) regions. Although TAAs and AAAs develop in the same ‘conduit’, they have distinctively contrasting characteristics. For example, TAAs occur in patients of all ages, are equivalent in both genders, and frequently have a known genetic basis. By contrast, AAAs are most prevalent in the aged male population without an overt genetic basis. In

Cellular and intracellular interactions of AngII and TGF-β

AngII exerts its bioactive effects on vascular physiology and pathology predominantly through binding to AT1 receptors. In rodents, chromosomal duplication leads to expression of two isoforms, termed AT1a and AT1b. AT1a receptors are the primary determinant of AngII effects in rodents. AngII-AT1 receptor interactions induce multiple signaling pathways not only in cell types resident in the aortic wall including smooth muscle and endothelial cells but also in infiltrating leukocytes [2].

Interactions of AngII and TGF-β in TAAs

Current literature is consistent with the premise of the RAS contributing to experimental and human TAA formation. Direct experimental evidence has been garnered from studies demonstrating that chronic subcutaneous AngII infusion promotes TAAs [13]. These TAAs are predominantly localized to the ascending aortic region, although there are pathological changes that extend throughout the aortic arch. Dilation of the ascending aorta occurs progressively during continued AngII infusion [14]. The

Interaction of AngII and TGF-β in AAAs

There is uncertainty regarding the role of the RAS in human AAAs. Clarification of this role could be obtained through clinical trials that test pharmacologic approaches currently available for blocking the RAS, such as inhibitors of renin, ACE, or AT1 receptors. Despite the uncertainty regarding the role of the RAS in human AAAs, many animal studies have demonstrated that chronic AngII infusion promoted development of AAAs in both normocholesterolemic and hypercholesterolemic mice [1].

Conclusions and perspectives

The current literature consistently demonstrates that AngII infusion promotes development of both TAAs and AAAs in mouse models. There is also consistency of the effects of AT1 receptor antagonism in reducing TAAs and AAAs induced by AngII infusion or genetic manipulations of fibrillin-1. However, as reported, roles of TGF-β in regulating these AngII provoked responses range from TGF-β neutralization being highly detrimental to beneficial. Given the current uncertainty for the role of TGF-β in

Acknowledgements

The authors’ research work was supported by funding from the National Institutes of Health (HL062846 and HL107319). Xiaofeng Chen's research was also supported by a McKusick Fellowship grant from the National Marfan Foundation (NMF).

References (35)

  • X.H. Zhang et al.

    TGF-beta1 downregulates AT1 receptor expression via PKC-delta-mediated Sp1 dissociation from KLF4 and Smad-mediated PPAR-gamma association with KLF4

    Arterioscler Thromb Vasc Biol

    (2012)
  • B. Schmierer et al.

    TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility

    Nat Rev Mol Cell Biol

    (2007)
  • A. Bobik

    Transforming growth factor-betas and vascular disorders

    Arterioscler Thromb Vasc Biol

    (2006)
  • J. Rodriguez-Vita et al.

    Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanism

    Circulation

    (2005)
  • W. Wang et al.

    Essential role of Smad3 in angiotensin II-induced vascular fibrosis

    Circ Res

    (2006)
  • A. Daugherty et al.

    Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE−/− mice

    Clin Sci (Lond)

    (2010)
  • D.L. Rateri et al.

    Endothelial cell-specific deficiency of Ang II type 1a receptors attenuates Ang II-induced ascending aortic aneurysms in LDL receptor−/− mice

    Circ Res

    (2011)

    • Cited by (0)

    View full text
    Copyright © 2013 Elsevier Ltd. All rights reserved.