Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation

Filiberto, Amanda C.; Spinosa, Michael; Elder, Craig T.; Su, Gang; Leroy, Victoria; Ladd, Zachary; Lu, Guanyi; Mehaffey, J. Hunter; Salmon, Morgan; Hawkins, Robert B.; Ravichandran, Kodi S.; Isakson, Brant E.; Upchurch, Gilbert R.; Sharma, Ashish K.

doi:10.1038/s41467-022-29233-4

Cited by 43 publications

(42 citation statements)

References 65 publications

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“…Intercellular communication between SMCs and NVU cells relies on Cxs-based and pannexin-based channels which, acting as ATP and calcium channels, modulates vascular remodeling and cell migration [ 142 ]. Recent reports regarding SMCs Cxs signatures show that SMCs actively express Cx43-based channels, even if their role seems strictly context dependent and not fully elucidated (particularly their role in inhibiting SMCs autophagy) [ 143 ].…”

Section: Connexins Signatures Of Nvu Componentsmentioning

confidence: 99%

Connexins Signatures of the Neurovascular Unit and Their Physio-Pathological Functions

Vicario

Parenti

2022

IJMS

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Central nervous system (CNS) homeostasis is closely linked to the delicate balance of the microenvironment in which different cellular components of the neurovascular unit (NVU) coexist. Intercellular communication plays a pivotal role in exchanges of signaling molecules and mediators essential for survival functions, as well as in the removal of disturbing elements that can lead to related pathologies. The specific signatures of connexins (Cxs), proteins which form either gap junctions (GJs) or hemichannels (HCs), represent the biological substrate of the pathophysiological balance. Connexin 43 (Cx43) is undoubtedly one of the most important factors in glia–neuro–vascular crosstalk. Herein, Cxs signatures of every NVU component are highlighted and their critical influence on functional processes in healthy and pathological conditions of nervous microenvironment is reviewed.

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Section: Connexins Signatures Of Nvu Componentsmentioning

confidence: 99%

Connexins Signatures of the Neurovascular Unit and Their Physio-Pathological Functions

Vicario

Parenti

2022

IJMS

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“…TLRs bind to RAGEs to amplify the inflammatory response, an important mechanism that promotes atherosclerosis ( 11 ), and HMGB1 is the only known receptor with the highest affinity. Additionally, HMGB1 is also considered to be a neoendothelial mediator that stimulates vascular smooth muscle cell proliferation and migration ( 12 ). These data suggest that HMGB1 may be involved in the pathological process of restenosis after intervention.…”

Section: Introductionmentioning

confidence: 99%

The clinical significance of serum HMGB1 in patients with lower extremity arteriosclerosis obliterans after interventional vascular restenosis

Yang

Zhang²

2023

Front. Surg.

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ObjectiveThis study explored the correlation between serum HMGB1 levels and postoperative vascular restenosis in patients with lower extremity arteriosclerosis obliterans (LEASO).MethodsA total of 362 patients LEASO who received vascular intervention were recruited in this study. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay. Logistic regression analysis was used to identify the influencing factors associated with vascular restenosis. The R procedure was used to create nomogram model. Receiver operating characteristic (ROC) analysis was used to determine the predictive value of serum HMGB1 and nomogram model for vascular restenosis.ResultsOf the 362 LEASO patients included, 103 (28.45%) developed restenosis within 6 months of postoperative follow-up. Postoperative HMGB1 levels were significantly higher in patients with restenosis compared to those with non-restenosis. Postoperative HMGB1 levels were significantly and positively correlated with the severity of postoperative restenosis (r = 0.819). The AUC of postoperative HMGB1 for the diagnosis of postoperative restenosis was 0.758 (95% CI: 0.703–0.812), with a sensitivity and specificity of 56.31% and 82.24%, respectively. Multivariate logistic regression analysis showed that diabetes, smoking, regular postoperative medication, increased fibrinogen, decreased red blood cells, increased hs-CRP, and increased postoperative HMGB1 were independently associated with postoperative restenosis in patients with LEASO. The C-index of the nomogram prediction model constructed based on the seven influencing factors mentioned above was 0.918. The nomogram model was significantly more predictive of postoperative restenosis in LEASO patients compared with a single postoperative HMGB1 (AUC: 0.918, 95% CI: 0.757–0.934).ConclusionPostoperative serum HMGB1 is an independent risk factor associated with postoperative vascular restenosis in patients with LEASO, and a novel nomogram model based on postoperative serum HMGB1 combined with clinical characteristics may help to accurately predict the risk of postoperative restenosis in patients with LEASO.

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“…An important role for Panx1 in inflammation has been observed especially for endothelial cells, because Panx1 at the plasma membrane of these cells mediates vascular inflammation during lung ischemia-reperfusion injury (25) and regulates cardiac responses to acute myocardial infarction (26). Thus, it is not surprising that endothelial cell specific Panx1 deficiency but not smooth muscle cell specific Panx1 deficiency resulted in reduced AAA formation compared to respective WT mice in the topical PPE model (12). The authors detected reduced acute phase cytokines such as HMGB1, IL-17, MCP1 and TNFα in Panx1 deficient mice compared to elastase-treated control mice.…”

Section: Discussionmentioning

confidence: 99%

“…These mice displayed decreased elastic fibre disruption compared to their respective controls. Application of the Panx1 inhibitor Prb to PPE mice inhibited leukocyte transmigration, aortic inflammation and remodeling to attenuate AAA formation (12). All these data suggest a major contribution of Panx1 channels in inflammation and AAA formation with a dominant role of endothelial Panx1 in these processes.…”

Section: Discussionmentioning

confidence: 99%

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Platelet pannexin-1 channels modulate inflammation during abdominal aortic aneurysm formation

Metz

Feige

Biasi

et al. 2022

Preprint

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Abdominal aortic aneurysm (AAA) is a common disease and highly lethal if untreated. The progressive dilatation of the abdominal aorta is accompanied by degradation and remodeling of the vessel wall due to chronic inflammation. Pannexins represent anion-selective channels and play a crucial role in non-vesicular ATP release to amplify paracrine signaling in cells. Thus, pannexins are involved in many (patho-) physiological processes. Recently, Panx1 channels were identified to be significantly involved in AAA formation through endothelial derived Panx1 regulated inflammation and aortic remodeling. In platelets, Panx1 becomes activated following activation of glycoprotein (GP)VI. Since platelets play a role in cardiovascular diseases including AAA, we analyzed the contribution of platelet Panx1 in the progression of AAA. We detected enhanced Panx1 plasma levels in AAA patients. In experimental AAA using the pancreatic porcine elastase (PPE) mouse model, a major contribution of platelet Panx1 channels in platelet activation, pro-coagulant activity of platelets and platelet-mediated inflammation has been detected. In detail, platelets are important for the migration of neutrophils into the aortic wall induced by direct cell interaction and by activation of endothelial cells. Decreased platelet activation and inflammation did not affect ECM remodeling or wall thickness in platelet-specific Panx1 knock-out mice following PPE surgery. Thus, aortic diameter expansion at different time points after elastase infusion of the aortic wall was unaltered in platelet-specific Panx1 deficient mice suggesting that the modulation of inflammation alone does not affect AAA formation and progression. In conclusion, our data strongly supports the role of platelets in inflammatory responses in AAA via Panx1 channels and adds important knowledge about the significance of platelets in AAA pathology important for the establishment of an anti-platelet therapy for AAA patients.

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Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation

Cited by 43 publications

References 65 publications

Connexins Signatures of the Neurovascular Unit and Their Physio-Pathological Functions

Connexins Signatures of the Neurovascular Unit and Their Physio-Pathological Functions

The clinical significance of serum HMGB1 in patients with lower extremity arteriosclerosis obliterans after interventional vascular restenosis

Platelet pannexin-1 channels modulate inflammation during abdominal aortic aneurysm formation

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