Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) by vascular smooth muscle cells. Deficiency in MMP3 reduces ECM damage and the susceptibility of mice to develop AAA. Here, we establish netrin-1 as a major signal that mediates the dynamic crosstalk between inflammation and chronic erosion of the ECM in AAA.

Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) is undefined. Here we show defective mechano-phenotype signatures of VSMC in AAA measured with ultrasound tweezers-based micromechanical system and single-cell RNA sequencing technique. Theoretical modelling predicts that cytoskeleton alterations fuel cell membrane tension of VSMC, thereby modulating their mechanoallostatic responses which are validated by live micromechanical measurements. Mechanistically, VSMC gradually adopt a mechanically solid-like state by upregulating cytoskeleton crosslinker, α-actinin2, in the presence of AAA-promoting signal, Netrin-1, thereby directly powering the activity of mechanosensory ion channel Piezo1. Inhibition of Piezo1 prevents mice from developing AAA by alleviating pathological vascular remodeling. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel culprit of mechanically fatigued aorta in AAA.

SUMMARY Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3 −/− mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.

Objectives: We aimed at comparing the acute performance of bioresorbable scaffolds (BRS) and second-generation drug-eluting stents (DES) for the treatment of chronic total occlusions (CTO). Background: There is a lack of knowledge regarding the use of BRS in CTO. Methods: Key outcomes of interest were technical and procedural success. Technical success was defined as successful stent delivery and implantation, postprocedural residual diameter stenosis <30% within the treated segment, and restoration of thrombolysis in myocardial infarction (TIMI) grade 3 flow. Procedural success was defined as technical success with no in-hospital major adverse cardiac events (MACE). Results: Between May 2013 and May 2014, 32 patients underwent CTO percutaneous coronary intervention (PCI) with the Absorb BRS (Abbott Vascular, Santa Clara, CA) and were compared with a historical control group of 54 patients who had undergone CTO PCI with second-generation DES. Baseline characteristics were similar between the BRS and DES groups, with the exception of a larger mean reference vessel diameter in the BRS group (2.92 6 0.34 vs 2.50 6 0.68; P < 0.001). Technical success was less likely to be achieved in the BRS group compared with the DES group (78.1% vs 96.3%, P 5 0.012). Procedural success rates were 78.1% and 94.4% in the BRS and DES group, respectively (P 5 0.035). Conclusions: Compared with second-generation DES for PCI of CTO lesions, BRS were associated with lower rates of technical and procedural success. Catheterization and Cardiovascular Interventions 00:00-00 (2016) both prognosis and angina relief, with additional advantages including improvements in left ventricle function and reverse remodeling [1][2][3]. Introduction of new techniques and dedicated devices has significantly increased the procedural success rate of CTO PCI over the last years. In parallel, angiographic and clinical outcomes of CTO PCI have clearly benefited from the introduction of second-generation drug-eluting stents (DES) [4,5]. However, stenting a CTO with DES typically requires placement of long chains of metal (i.e., "full-metal jacket"), resulting in augmented risk of restenosis at mid-term and long term, permanent impairment of vasomotion and positive remodeling, technical artifacts at noninvasive cardiac imaging, and inability for later placement of bypass grafts if necessary.Bioresorbable scaffolds (BRS) hold characteristics that make them ideal devices after CTO recanalization, in that they provide a temporary mechanical support to the vessel wall followed by complete bioresorption over the long term [6]. However, data regarding the use of BRS in CTO lesions are sparse [7,8]. Early clinical experiences provide preliminary evidence of feasibility and early efficacy, but none of these studies has compared the acute performance of the BRS with that of second-generation DES in the setting of CTO PCI. Indeed, having a reliable and "standard of care" comparator is crucial when assessing the performance of a new device. On this background, the aim o...

Thoracic aortic aneurysm (TAA) is a complex life-threatening disease characterized by extensive extracellular matrix (ECM) fragmentation and persistent inflammation, culminating in a weakened aorta. Although evidence suggests defective canonical signaling pathways in TAA, the full spectrum of mechanisms contributing to TAA is poorly understood, therefore limiting the scope of drug-based treatment. Here, we used a sensitive RNA sequencing approach to profile the transcriptomic atlas of human TAA. Pathway analysis revealed upregulation of key matrix-degrading enzymes and inflammation coincident with the axonal guidance pathway. We uncovered their novel association with TAA and focused on the expression of Semaphorins and Netrins. Comprehensive analysis of this pathway showed that several members were differentially expressed in TAA compared to controls. Immunohistochemistry revealed that Semaphorin4D and its receptor PlexinB1, similar to Netrin-1 proteins were highly expressed in damaged areas of TAA tissues but faintly detected in the vessel wall of non-diseased sections. It should be considered that the current study is limited by its sample size and the use of internal thoracic artery as control for TAA for the sequencing dataset. Our data determines important neuronal regulators of vascular inflammatory events and suggest Netrins and Semaphorins as potential key contributors of ECM degradation in TAA.

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After a failed antegrade approach, the anterolateral retrograde puncture of the P3 or of the TPT is a valuable and safe technique to treat femoropopliteal CTOs in selected patients, regardless the distal spread of the lesion to the popliteal artery.