Construction of a high-throughput aorta smooth muscle-on-a-chip for thoracic aortic aneurysm drug screening.

Thoracic aortic aneurysm (TAA), in which arteries enlarge asymptomatically over time until dissection or rupture occurs, is a serious health risk. The mainstay of TAA treatment remains surgical repair due to the lack of effective drugs. The complex etiology and pathogenesis of TAA, including hemodynamic alterations and genetic factors, lead to inaccuracies in preclinical models for drug screening. Previously, our group designed an aorta smooth muscle-on-a-chip to emulate human aorta physiology and pathophysiology and screened three promising therapeutic drugs targeting mitochondrial dynamics in TAA. On this foundation, we updated the one-channel chip to an eighteen-well chip platform with four polydimethylsiloxane layers. Benefiting from this high-throughput chip, we rapidly screened multiple drugs simultaneously using distinct cell lines in vitro. In addition, we observed the abnormal activation of hypoxia-inducible factor 1-alpha (HIF-1alpha) in aortas from TAA patients by Western blot and bioinformatics analyses. Intriguingly, this phenomenon was replicated only when smooth muscle cells (SMCs) were strained on the chip. We then screened seven specific HIF-1alpha inhibitors and selected the two most effective drugs (2-methoxyestradiol and digoxin) by quantitative PCR and colorimetric methods. The results demonstrated that these two drugs can improve respiratory chain function and rescue the SMC contractile phenotype, showing applicability for the clinical treatment of TAA. This high-throughput aorta smooth muscle-on-a-chip will become a potential preclinical model for TAA drug screening.

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

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.

Paradigm for Detecting Silent Thoracic Aneurysm Disease.

Thoracic aortic aneurysms (TAA) pose a serious detection challenge owing to their clinically silent nature. Only a small fraction of TAAs cause symptoms in patients. However, the mortality burden of this disease in the population is significant, given the high lethality of such complications as aortic rupture and dissection. Widespread screening for TAA has not been shown to be cost-effective. Therefore, currently most patients with a TAA are identified incidentally during an imaging study conducted for other reasons. Once a TAA diagnosis is established, prophylactic surgical treatment can safely be performed for aneurysms of the ascending aorta, aortic arch, and descending or thoracoabdominal aorta, thus preventing aneurysm-related death. To facilitate early detection of TAA, recent studies have identified several "associates" of TAA that may be useful in making a timely diagnosis. These "associates" include intracranial aneurysm, aortic arch anomalies, abdominal aortic aneurysm, simple renal cysts, bicuspid aortic valve, temporal arteritis, a positive family history of aneurysm disease, and a positive thumb-palm sign, among others. Although for many of these "associates" the underlying mechanism that would explain the association remains to be elucidated, the clinical correlation is strong enough to suggest screening patients with these findings for TAA. This article introduces the "Guilt by Association" paradigm for detection of silent thoracic aortic disease based on detection of clinical markers associated with this condition.