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-ß (TGF-ß) 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 ß-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-ß 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 ß-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Aortic Aneurysm, Thoracic/drug therapy , Aortic Aneurysm, Thoracic/pathology , Renin-Angiotensin System/physiology , Transforming Growth Factor beta/metabolism , Adrenergic beta-Antagonists/pharmacology , Angiotensin Receptor Antagonists/pharmacology , Animals , Aortic Aneurysm, Thoracic/genetics , Clinical Trials as Topic , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , MAP Kinase Signaling System/physiology , Mice , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/metabolism , Renin-Angiotensin System/drug effects , Signal Transduction/physiology , Syndrome , Transforming Growth Factor beta/drug effectsABSTRACT
Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1Δ/- mice, can be used as a tool to accelerate aging. Ercc1Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1Δ/- mice. Ercc1Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1Δ/- mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.