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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. Here, we report that abnormal upregulation of angiotensin converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling is 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, aortic aneurysms, and development and maintenance of the SMC phenotype.

Unraveling the normal physiologic role of β-amyloid is likely crucial to understanding the pathogenesis of Alzheimer's disease. However, progress on this question is currently limited by the high background of many ELISAs for murine β-amyloid. Here, we examine the background signal of several murine β-amyloid ELISAs, and conclude that the majority of the background is from non-APP derived proteins. Most importantly, we identify ELISAs that eliminate this background signal.

Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease.

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