Sepsis modulates aortic AT1 and P<sub>2</sub>Y<sub>6</sub> receptors to produce vascular hyporeactivity in mice

Jagadeesh, T; Choudhury, Soumen; Gari, Manju; Singh, Vandana; Shukla, Aditya; Garg, Satish K.

doi:10.1080/10799893.2023.2204960

Cited by 3 publications

(3 citation statements)

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“…Severe sepsis is characterized by peripheral vasodilation, hypotension accompanied by multiorgan failure and high mortality [ 62 ]; however, the mechanisms are not fully clarified. It is reported that sepsis/LPS can upregulate iNOS expression and stimulate tissues to produce NO, which critically mediates the sepsis-induced vascular hyporeactivity response to Ang II, and this effect is significantly reversed by iNOS inhibitors in septic mice, implying that NO is a key mechanism for septic hypotension [ [63] , [64] , [65] ]. The RAAS plays central roles in vascular and blood pressure homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…However, other studies indicate that the use of Ang II is not able to restore sepsis-related hypotension, but is associated with organ damage and high mortality in septic patients [ 69 ]. Interestingly, sepsis reduces AT1R expression in rats and mice [ 63 , 65 ], and sepsis-related production of proinflammatory cytokines and NO can influence AT1R expression or Ang II binding activity [ 70 , 71 ]. The combination of proinflammatory cytokines (IL-1β, TNF-a and IFN-γ) markedly reduces Ang II binding to AT1R in rat renal mesangial cells [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

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Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1–7)-Mas-mediated macrophage polarization

Li,

Xiao,

Teng

et al. 2024

Redox Biology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1–7)-Mas-mediated macrophage polarization

Li,

Xiao,

Teng

et al. 2024

Redox Biology

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“…While studies support a role for genetic (243)(244)(245)(246)(247)(248) and epigenetic (249)(250)(251)(252)(253)(254)(255) factors in sepsis, the topic remains relatively unexplored. Despite years of research in this domain, we do not yet fully understand the link between genetic factors and susceptibility, severity and evolution of sepsis.…”

Section: Bts5: How Do Genetics and Epigenetics Influence The Developm...mentioning

confidence: 99%

Surviving Sepsis Campaign Research Priorities 2023

De Backer,

Deutschman,

Hellman

et al. 2024

Critical Care Medicine

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OBJECTIVES: To identify research priorities in the management, epidemiology, outcome, and pathophysiology of sepsis and septic shock. DESIGN: Shortly after publication of the most recent Surviving Sepsis Campaign Guidelines, the Surviving Sepsis Research Committee, a multiprofessional group of 16 international experts representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine, convened virtually and iteratively developed the article and recommendations, which represents an update from the 2018 Surviving Sepsis Campaign Research Priorities. METHODS: Each task force member submitted five research questions on any sepsis-related subject. Committee members then independently ranked their top three priorities from the list generated. The highest rated clinical and basic science questions were developed into the current article. RESULTS: A total of 81 questions were submitted. After merging similar questions, there were 34 clinical and ten basic science research questions submitted for voting. The five top clinical priorities were as follows: 1) what is the best strategy for screening and identification of patients with sepsis, and can predictive modeling assist in real-time recognition of sepsis? 2) what causes organ injury and dysfunction in sepsis, how should it be defined, and how can it be detected? 3) how should fluid resuscitation be individualized initially and beyond? 4) what is the best vasopressor approach for treating the different phases of septic shock? and 5) can a personalized/precision medicine approach identify optimal therapies to improve patient outcomes? The five top basic science priorities were as follows: 1) How can we improve animal models so that they more closely resemble sepsis in humans? 2) What outcome variables maximize correlations between human sepsis and animal models and are therefore most appropriate to use in both? 3) How does sepsis affect the brain, and how do sepsis-induced brain alterations contribute to organ dysfunction? How does sepsis affect interactions between neural, endocrine, and immune systems? 4) How does the microbiome affect sepsis pathobiology? 5) How do genetics and epigenetics influence the development of sepsis, the course of sepsis and the response to treatments for sepsis? CONCLUSIONS: Knowledge advances in multiple clinical domains have been incorporated in progressive iterations of the Surviving Sepsis Campaign guidelines, allowing for evidence-based recommendations for short- and long-term management of sepsis. However, the strength of existing evidence is modest with significant knowledge gaps and mortality from sepsis remains high. The priorities identified represent a roadmap for research in sepsis and septic shock.

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How selective antagonists and genetic modification have helped characterise the expression and functions of vascular P2Y receptors

Dales,

Drummond,

Kennedy

2024

Purinergic Signalling

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Vascular P2Y receptors mediate many effects, but the role of individual subtypes is often unclear. Here we discuss how subtype-selective antagonists and receptor knockout/knockdown have helped identify these roles in numerous species and vessels. P2Y1 receptor-mediated vasoconstriction and endothelium-dependent vasodilation have been characterised using the selective antagonists, MRS2179 and MRS2216, whilst AR-C118925XX, a P2Y2 receptor antagonist, reduced endothelium-dependent relaxation, and signalling evoked by UTP or fluid shear stress. P2Y2 receptor knockdown reduced endothelial signalling and endothelial P2Y2 receptor knockout produced hypertensive mice and abolished vasodilation elicited by an increase in flow. UTP-evoked vasoconstriction was also blocked by AR-C118925XX, but the effects of P2Y2 receptor knockout were complex. No P2Y4 receptor antagonists are available and P2Y4 knockout did not affect the vascular actions of UTP and UDP. The P2Y6 receptor antagonist, MRS2578, identified endothelial P2Y6 receptors mediating vasodilation, but receptor knockout had complex effects. MRS2578 also inhibited, and P2Y6 knockout abolished, contractions evoked by UDP. P2Y6 receptors contribute to the myogenic tone induced by a stepped increase in vascular perfusion pressure and possibly to the development of atherosclerosis. The P2Y11 receptor antagonists, NF157 and NF340, inhibited ATP-evoked signalling in human endothelial cells. Vasoconstriction mediated by P2Y12/P2Y13 and P2Y14 receptors was characterised using the antagonists, cangrelor, ticagrelor, AR-C67085 and MRS2211 or PPTN respectively. This has yet to be backed up by receptor knockout experiments. Thus, subtype-selective antagonists and receptor knockout/knockdown have helped identify which P2Y subtypes are functionally expressed in vascular smooth muscle and endothelial cells and the effects that they mediate.

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Sepsis modulates aortic AT1 and P₂Y₆ receptors to produce vascular hyporeactivity in mice

Cited by 3 publications

References 54 publications

Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1–7)-Mas-mediated macrophage polarization

Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1–7)-Mas-mediated macrophage polarization

Surviving Sepsis Campaign Research Priorities 2023

How selective antagonists and genetic modification have helped characterise the expression and functions of vascular P2Y receptors

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Sepsis modulates aortic AT1 and P2Y6 receptors to produce vascular hyporeactivity in mice

Cited by 3 publications

References 54 publications

Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1–7)-Mas-mediated macrophage polarization

Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1–7)-Mas-mediated macrophage polarization

Surviving Sepsis Campaign Research Priorities 2023

How selective antagonists and genetic modification have helped characterise the expression and functions of vascular P2Y receptors

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Sepsis modulates aortic AT1 and P₂Y₆ receptors to produce vascular hyporeactivity in mice