Angiotensin-Converting Enzyme–Induced Activation of Local Angiotensin Signaling Is Required for Ascending Aortic Aneurysms in Fibulin-4–Deficient Mice

Up-regulation of angiotensin-converting enzyme in the aortic wall causes aneurysms in fibulin-4–deficient mice, which can be prevented by losartan or captopril. ACEing Aortic Aneurysm Prevention Aortic aneurysms, areas of abnormal dilation of the aorta, can be a fast and unexpected killer, striking unsuspecting patients without previous warning. These aneurysms can occur in patients with atherosclerosis, or even without any known risk factors, but they are particularly common in patients with Marfan syndrome and other types of connective tissue disease. Now, Huang et al. have created a mouse model of genetic predisposition to ascending aortic aneurysms and used it to test potential therapeutic interventions. The mouse model presented by the authors lacks expression of fibulin-4 in vascular smooth muscle cells. Fibulin-4 normally contributes to the structure of elastic fibers and the contractile phenotype of smooth muscle cells in the vasculature. Mutations in the Fbln4 gene have been implicated in human connective tissue disease. The mice lacking vascular fibulin-4 protein predictably developed ascending aortic aneurysms early in life, and their blood vessel walls had a disorganized structure and disrupted elastic fibers. The authors showed that these mice also expressed abnormally high amounts of angiotensin-converting enzyme (ACE) in their ascending aortas, which caused abnormal extracellular signal–regulated kinase signaling through activation of angiotensin receptor 1. When the mutant animals were treated with captopril (an ACE inhibitor) or losartan (an angiotensin receptor blocker), thus interfering with the excess angiotensin signaling early in life, the aortic aneurysms did not develop. This work by Huang and coauthors clarifies a mechanism of aortic aneurysm formation and provides some insight into a potential approach for intervention. Additional work will be needed to determine how much of this mechanism holds true in human patients (and in which subpopulations) and what intervention can help treat aneurysms after they have already formed. Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4SMKO) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4SMKO mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4SMKO mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.