Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress inApln−/yaorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater inApln−/ymice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture inApln−/ymice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) inLdlr−/−mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

Objective Reduced blood flow and/or tissue oxygen tension conditions result from thrombotic and vascular diseases such as myocardial infarction, stroke, and peripheral vascular disease. It is largely assumed that while platelet activation is increased by an acute vascular event, chronic vascular inflammation, and/or ischemia, the platelet activation pathways and responses are not themselves changed by the disease process. We therefore sought to determine whether the platelet phenotype is altered by hypoxic and ischemic conditions. Approach and Results In a cohort of patients with metabolic and peripheral artery disease (PAD), platelet activity was enhanced and/or inhibition with oral anti-platelet agents was impaired compared to platelets from control subjects, suggesting a difference in platelet phenotype caused by disease. Isolated murine and human platelets exposed to reduced oxygen (hypoxia chamber, 5% O2) had increased expression of some proteins that augment platelet activation compared to platelets in normoxic conditions (21% O2). Using a murine model of critical limb ischemia (CLI), platelet activity was increased even two weeks post-surgery compared to sham surgery mice. This effect was partly inhibited in platelet specific Extracellular Regulated Protein Kinase 5 (ERK5) knockout mice. Conclusions These findings suggest that ischemic disease changes the platelet phenotype and alters platelet agonist responses due to changes in the expression of signal transduction pathway proteins. Platelet phenotype and function should therefore be better characterized in ischemic and hypoxic diseases to understand the benefits and limitations of anti-platelet therapy.

Transabdominal ultrasound elasticity imaging could improve the assessment of rupture risk for abdominal aortic aneurysms by providing information on the mechanical properties and stress or strain states of vessel walls. We implemented a non-rigid image registration method to visualize the pressure-normalized strain within vascular tissues and adapted it to measure total strain over an entire cardiac cycle. We validated the algorithm’s performance with both simulated ultrasound images with known principal strains and anatomically accurate heterogeneous polyvinyl alcohol cryogel vessel phantoms. Patient images of abdominal aortic aneurysm were also used to illustrate the clinical feasibility of our imaging algorithm and the potential value of pressure-normalized strain as a clinical metric. Our results indicated that pressure-normalized strain could be used to identify spatial variations in vessel tissue stiffness. The results of this investigation were sufficiently encouraging to warrant a clinical study measuring abdominal aortic pressure-normalized strain in a patient population with aneurysmal disease.

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