Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes

Souilhol, Céline; Serbanovic-Canic, Jovana; Fragiadaki, Maria; Chico, Timothy J. A.; Ridger, Victoria; Roddie, Hannah; Evans, Paul C.

doi:10.1038/s41569-019-0239-5

Cited by 314 publications

(237 citation statements)

References 180 publications

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“…Atherosclerosis, one of the leading causes of cardiovascular morbidity and mortality, is a chronic inflammatory vascular disease [19]. More and more evidences have indicated that not only the formation and progression but also the rupture of atherosclerotic plaques could be drove by inflammation [20].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Yang

Jia

et al. 2020

BMC Cardiovasc Disord

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Background: Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. In this study, we designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process.Methods: Atherosclerosis was induced in the abdominal arteries of rabbits by balloon injury of the aorta supplemented by the atherogenic diet. Simultaneously, in the process of atherosclerosis, animals underwent either ruxolitinib treatment or not for 12 weeks. At the end of the experimental period, all rabbits were sacrificed. The plaque areas in abdominal artery, the lipid burden of plaque and the calcium burden of plaque were detected by H&E staining, Oil Red O staining and Alizarin Red staining, respectively. In addition, rabbit plasma lipids and inflammatory cytokines were measured by biochemical test kits or ELISA kits. Finally, the expression and phosphorylation levels of JAK2/STAT3/SOCS3 pathway-related proteins were detected by RT-qPCR, western blot and immunohistochemistry assays.Results: H&E staining and CT scan analysis showed that rabbit atherosclerosis model was constructed successfully. Ruxolitinib, an inhibitor of the Janus kinase 2 (JAK2), substantially reduced the area of atherosclerotic plaques in rabbits treated with high fat diet and balloon injury of the aorta. Moreover, ruxolitinib significantly decreased IL-6, IL-1β, IFN-γ and TNF-α, but increased IL-10 and IL-17 levels in plasma of atherosclerotic rabbits. Additionally, ruxolitinib reduced plasma TC, TG and LDL-C contents and AIP value, while enhanced HDL-C level in atherosclerotic rabbits. Furthermore, we found that JAK2 and STAT3 phosphorylation were up-regulated in rabbits with atherosclerosis when compared with those of the control group, followed by the expression of SOCS3 was also increased due to the activation of JAK2 and STAT3. Interestingly, ruxolitinib could inactivate JAK2 and STAT3 pathway and decrease SOCS3 expression.Conclusion: Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Yang

Jia

et al. 2020

BMC Cardiovasc Disord

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“…Atherosclerosis, as a major vascular disease, is a progressive illness caused by inflammatory events in endothelial cells (ECs) of large or medium arteries 1 . The EC monolayer, located at the interface between the circulating blood and vessel wall, is directly exposed to blood flow and associated shear stress 2 . Shear stress plays crucial roles in the maintenance and disturbance of vascular homeostasis, and different flows greatly modify endothelial phenotypes and determine the uneven distribution of atherosclerotic lesions 3 .…”

Section: Introductionmentioning

confidence: 99%

Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis

Yuan

et al. 2020

Cell Death Dis

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Atherosclerosis is a multifactorial disease of the vasculature, and shear stress is a crucial regulator of its process. Disturbed flow promotes atherosclerotic effects, while laminar flow has a protective action on the endothelium. Hippo/YAP is a major cascade that senses various mechanical cues and mediates the expression of pro-inflammatory genes. However, the mechanism modulating the transcription factor YAP in response to different patterns of blood flow remains unclear. In this study, we provide evidence that shear stress modulates YAP activity via autophagy in endothelial cells. Laminar flow promoted the expression of the autophagic markers BECLIN 1 and LC3II/LC3I. Autophagy blockade using a chemical inhibitor repressed YAP degradation under laminar flow. Conversely, the induction of autophagy under disturbed flow partially antagonized the nuclear import and transcriptional activation of YAP. In parallel, laminar flow led to the increased expression of SIRT1 protein, a NAD +-dependent deacetylase. Further investigation showed that SIRT1-mediated YAP deacetylation. The forced expression of SIRT1 under disturbed flow effectively attenuated YAP activation and nuclear accumulation, thereby downregulating the expression of proinflammatory genes. In atheroprone vessels of mice receiving rapamycin to induce autophagy, the enhanced expression of SIRT1 was observed together with YAP repression. Altogether, these results show that endothelial autophagy and SIRT1 expression induced by laminar flow contribute to the inhibition of Hippo/YAP signaling and interrupt atherosclerotic plaque formation.

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“…With the progression of age, dysregulation of physiological functions, and accumulation of chronic stress, multiple vascular abnormalities gradually arise, mainly arteriosclerosis, atherosclerosis, thrombosis, and fibrosis. [ 92,97,330 ] Arteriosclerosis refers to the stiffening of vessel walls due to reduced production of elastin and substitution with type I collagen in the intimal layer, primarily by VSMCs. Multiple causes including changes in shear stress, cyclic stretch, and prolonged hypertension have been implicated in the phenotypic switching of VSMCs, which also leads to dysregulation of vascular tone.…”

Section: Modeling Vascular Mechanopathology In Vascularized Microphysmentioning

confidence: 99%

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

Pradhan

Banda

Farino

et al. 2020

Adv Healthcare Materials

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The vascular system is integral for maintaining organ‐specific functions and homeostasis. Dysregulation in vascular architecture and function can lead to various chronic or acute disorders. Investigation of the role of the vascular system in health and disease has been accelerated through the development of tissue‐engineered constructs and microphysiological on‐chip platforms. These in vitro systems permit studies of biochemical regulation of vascular networks and parenchymal tissue and provide mechanistic insights into the biophysical and hemodynamic forces acting in organ‐specific niches. Detailed understanding of these forces and the mechanotransductory pathways involved is necessary to develop preventative and therapeutic strategies targeting the vascular system. This review describes vascular structure and function, the role of hemodynamic forces in maintaining vascular homeostasis, and measurement approaches for cell and tissue level mechanical properties influencing vascular phenomena. State‐of‐the‐art techniques for fabricating in vitro microvascular systems, with varying degrees of biological and engineering complexity, are summarized. Finally, the role of vascular mechanobiology in organ‐specific niches and pathophysiological states, and efforts to recapitulate these events using in vitro microphysiological systems, are explored. It is hoped that this review will help readers appreciate the important, but understudied, role of vascular‐parenchymal mechanotransduction in health and disease toward developing mechanotherapeutics for treatment strategies.

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Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes

Cited by 314 publications

References 180 publications

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

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