ABSTRACT
Peripheral artery disease (PAD) is the narrowing of the arteries that carry blood to the lower extremities. PAD has been traditionally associated with atherosclerosis. However, recent studies have found that medial arterial calcification (MAC) is the primary cause of chronic limb ischemia below the knee. MAC involves calcification of the elastin fibers surrounding smooth muscle cells (SMCs) in arteries. Matrix GLA Protein (MGP) binds circulating calcium and inhibits vascular calcification. Mgp -/- mice develop severe MAC and die within 8 weeks of birth due to aortic rupture or heart failure. We previously discovered a rare genetic disease Arterial Calcification due to Deficiency in CD73 (ACDC) in which patients present with extensive MAC in their lower extremity arteries. Using a patient-specific induced pluripotent stem cell model we found that rapamycin inhibited calcification. Here we investigated whether rapamycin could reduce MAC in vivo using Mgp -/- mice as a model. Mgp +/+ and Mgp -/- mice received 5mg/kg rapamycin or vehicle. Calcification content was assessed via microCT, and vascular morphology and extracellular matrix content assessed histologically. Immunostaining and western blot analysis were used to examine SMC phenotypes and cellular functions. Rapamycin prolonged Mgp -/- mice lifespan, decreased mineral density in the arteries, and increased smooth muscle actin protein levels, however, calcification volume, vessel morphology, SMC proliferation, and autophagy flux were all unchanged. These findings suggest that rapamycin's effects in the Mgp -/- mouse are independent of the vascular phenotype.
ABSTRACT
Management of intracranial aneurysms (IAs) is determined by patient age, risk of rupture, and comorbid conditions. While endovascular and microsurgical interventions offer solutions to mitigate the risk of rupture, pharmacological management strategies may complement these approaches or serve as alternatives in appropriate cases. The pathophysiology of IAs allows for the targeting of inflammation to prevent the development and rupture of IAs. The aim of this review is to provide an updated summary of different pharmaceutical management strategies for IAs. Acetylsalicylic acid and renin-angiotensin-aldosterone system (RAAS) inhibitor antihypertensives have some evidence supporting their protective effect. Studies of selective cyclooxygenase-2 (COX-2) inhibitors, statins, ADP inhibitors, and other metabolism-affecting drugs have demonstrated inconclusive findings regarding their association with aneurysm growth or rupture. In this manuscript, we highlight the evidence supporting each drug's effectiveness.
ABSTRACT
Shift work has emerged as a significant health concern in recent years, and research has revealed a link to circadian rhythm dysregulation and atherosclerosis, both of which can increase the risk of cardiovascular disease (CVD). Currently, there is a lack of updated reviews regarding the impact of shiftwork on CVD. Thus, the present narrative review aims to provide a comprehensive summary of the latest research on the relationship between shift work and CVD, identify potential gaps in the current knowledge, and highlight areas for future research. Database searches for peer-reviewed articles published between January 2013 to January 2023 on shift work associated CVD revealed many studies that found shift work is linked with increased prevalence of carotid artery plaque, increased arterial stiffness, and carotid artery intima-media thickness (IMT) all suggestive of a progression of atherosclerosis attributable to shift work. Hypertension, diabetes, and a sedentary lifestyle are known risks for CVD, and the results of the present study suggest that shift work should be added to that list. The elevation of inflammatory markers and DNA damage in shift workers may be linked to their increased progression of atherosclerosis and the positive association of shift work with coronary artery disease. There are minimal studies on mitigating approaches for shift work-related CVD, such as diet modification or exercise, emphasizing the need for further directed research in this area.
ABSTRACT
Arterial calcification due to deficiency of CD73 (ACDC) is a rare genetic disease caused by a loss-of-function mutation in the NT5E gene encoding the ecto-5'-nucleotidase (cluster of differentiation 73, CD73) enzyme. Patients with ACDC develop vessel arteriomegaly, tortuosity, and vascular calcification in their lower extremity arteries. Histological analysis shows that patients with ACDC vessels exhibit fragmented elastin fibers similar to that seen in aneurysmal-like pathologies. It is known that alterations in transforming growth factor ß (TGFß) pathway signaling contribute to this elastin phenotype in several connective tissue diseases, as TGFß regulates extracellular matrix (ECM) remodeling. Our study investigates whether CD73-derived adenosine modifies TGFß signaling in vascular smooth muscle cells (SMCs). We show that Nt5e-/- SMCs have elevated contractile markers and elastin gene expression compared with Nt5e+/+ SMCs. Ecto-5'-nucleotidase (Nt5e)-deficient SMCs exhibit increased TGFß-2 and activation of small mothers against decapentaplegic (SMAD) signaling, elevated elastin transcript and protein, and potentiate SMC contraction. These effects were diminished when the A2b adenosine receptor was activated. Our results identify a novel link between adenosine and TGFß signaling, where adenosine signaling via the A2b adenosine receptor attenuates TGFß signaling to regulate SMC homeostasis. We discuss how disruption in adenosine signaling is implicated in ACDC vessel tortuosity and could potentially contribute to other aneurysmal pathogenesis.