Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis

Chen, Runji; McVey, David G.; Shen, Daifei; Huang, Xiaoxin; Ye, Shu

doi:10.1161/jaha.123.031121

Cited by 13 publications

(7 citation statements)

References 99 publications

(216 reference statements)

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“…An intrinsic alteration of smooth muscle cell contraction‐relaxation dynamics is also an early change observed in our study, along with fibrogenic differentiation of SMCs, with reduced MYH11 and desmin expression and increased COL1A1 expression already evident in asymptomatic DIV. Altogether, our data provide unequivocal identification of a phenotypic switch 26,27 . Furthermore, the knowledge that phenotypic switch of SMCs can occur in the context of oxidative stress 28 further strengthens our hypothesis.…”

Section: Discussionsupporting

confidence: 78%

From diverticulosis to complicated diverticular disease: Progression of myogenic alterations and oxidative imbalance

Pallotta,

Pisano,

Vona

et al. 2024

Neurogastroenterology Motil

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BackgroundThe natural history and pathophysiology of diverticular disease (DD) are still uncertain. An ex‐vivo human complicated DD (cDD) model has recently shown a predominant transmural oxidative imbalance. The present study aims to evaluate whether the previously described alterations may precede the symptomatic form of the disease.MethodsColonic surgical samples obtained from patients with asymptomatic diverticulosis (DIV), complicated DD, and controls were systematically and detailed morphologically and molecularly analyzed. Therefore, histologic, histomorphometric, immunohistochemical evaluation, and gene and protein expression analysis were performed to characterize colonic muscle changes and evaluate chronic inflammation, oxidative imbalance, and hypoxia. Functional muscle activity was tested on strips and isolated cells in response to contractile and relaxant agents.Key ResultsCompared with controls, DD showed a marketed increase in muscle layer thickness, smooth muscle cell syncytium disarray, and increased interstitial fibrosis; moreover, the observed features were more evident in the cDD group. These changes mainly affected longitudinal muscle and were associated with altered contraction‐relaxation dynamics and fibrogenic switch of smooth muscle cells. Chronic lymphoplasmacytic inflammation was primarily evident in the mucosa and spared the muscle. A transmural increase in carbonylated and nitrated proteins, with loss of antioxidant molecules, characterized both stages of DD, suggesting early oxidative stress probably triggered by recurrent ischemic events, more pronounced in cDD, where HIF‐1 was detected in both muscle and mucosa.Conclusion & InferencesThe different DD clinical scenarios are part of a progressive process, with oxidative imbalance representing a new target in the management of DD.

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Section: Discussionsupporting

confidence: 78%

From diverticulosis to complicated diverticular disease: Progression of myogenic alterations and oxidative imbalance

Pallotta,

Pisano,

Vona

et al. 2024

Neurogastroenterology Motil

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“…Our data suggest that this may occur by promoting abnormal secretion of new matrix and preventing controlled degradation of abnormal matrix proteins. Interestingly, these conditions fit within the well-reported progression of fibrotic diseases, where an increase in matrix stiffness is accompanied by inflammation and a worse prognosis or clinical outcomes, such as in breast cancer (37), diabetes (38,39), and cardiovascular diseases (40,41). More importantly, this points to a potential target for cancer therapy (42), where the gradual fibrosis of the premalignant microenvironment that is known to promote malignant transformation may be therapeutically intercepted before the tumor-prone region becomes cancerous.…”

Section: Discussionsupporting

confidence: 74%

Perivascular cells function as mechano-structural sensors of vascular capillaries

Franca,

Lima Verde,

Silva-Sousa

et al. 2024

Preprint

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A wide range of conditions, including chronic inflammatory diseases and cancer, are characterized by the fibrotic microarchitecture and increased stiffness of collagen type I extracellular matrix. These conditions are typically accompanied by altered vascular function, including vessel leakiness, abnormal capillary morphology and stability. The dynamic cell-matrix interactions that regulate vascular function in healthy tissues have been well documented. However, our understanding of how the gradual mechanical and structural alterations in collagen type I affect vascular homeostasis remains elusive, especially as a function of the interactions between endothelial and perivascular cell with the altered matrix. Here we hypothesized that perivascular cells might function as mechano-structural sensors of the microvasculature by mediating the interaction between endothelial cells and altered collagen type I. To test that, we utilized an organotypic model of perivascular cell-supported vascular capillaries in collagen scaffolds of controlled microarchitecture and mechanics. Our results demonstrate that capillaries cultured in soft reticular collagen exhibited consistent pericyte differentiation, endothelial cell-cell junctions, and barrier function. In contrast, capillaries embedded in stiff and bundled collagen fibrils to mimic a more fibrotic matrix induced abluminal migration of perivascular cells, increased leakage, and marked expression of vascular remodeling and inflammatory markers. These patterns, however, were only observed when endothelial capillaries were engineered with perivascular cells. Silencing ofNOTCH3,a mediator of endothelial-perivascular cell communication, largely re-established normal vascular morphology and function. In summary, our findings point to a novel mechanism of perivascular regulation of vascular dysfunction in fibrotic tissues which may have important implications for anti-angiogenic and anti-fibrotic therapies in cancer, chronic inflammatory diseases and regenerative medicine.Significance StatementThe fibrotic alterations in extracellular matrix structure and mechanics that are common to many chronic and inflammatory conditions are often associated with a decrease in vascular homeostasis. The mechanisms regulating these abnormalities remain poorly understood. Here, we demonstrate that perivascular cells play a critical role in sensing progressive microarchitectural and mechanical changes occurring in the ECM, drastically altering vascular capillary morphology and barrier function, and exacerbating the production of inflammatory and remodeling markers. These results point to a previously unknown mechano-structural sensory mechanisms mediated by perivascular cells in vascular capillaries that may help elucidate the progression of many profibrotic conditions, and point to possible new targets for antiangiogenic and antifibrotic therapies in cancer, chronic inflammatory conditions and regenerative medicine.

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“…In addition to focusing on the side effect, we should also note that long-term inhibition of Skp2 may also have other beneficial effects when targeting non-cancer cells. For example, long-term inhibition of Skp2 may improve cardiovascular pathogenesis associated with abnormal proliferation of hepatic stellate cells and vascular smooth muscle cells, such as liver fibrosis (Medina Pizaño et al, 2023) and atherosclerosis (Chen et al, 2023b). Therefore, when using Skp2 inhibitors, the balance between the therapeutic effects and the side effects of Skp2 inhibitors may influence the final outcome of disease treatment.…”

Section: Discussionmentioning

confidence: 99%

NSC689857, an inhibitor of Skp2, produces antidepressant-like effects in mice

Liu,

Cheng,

et al. 2024

Behavioural Pharmacology

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We have previously reported that two inhibitors of an E3 ligase S-phase kinase-associated protein 2 (Skp2), SMIP004 and C1, have an antidepressant-like effect in non-stressed and chronically stressed mice. This prompted us to ask whether other Skp2 inhibitors could also have an antidepressant effect. Here, we used NSC689857, another Skp2 inhibitor, to investigate this hypothesis. The results showed that administration of NSC689857 (5 mg/kg) produced an antidepressant-like effect in a time-dependent manner in non-stressed male mice, which started 8 days after drug administration. Dose-dependent analysis showed that administration of 5 and 10 mg/kg, but not 1 mg/kg, of NSC689857 produced antidepressant-like effects in both non-stressed male and female mice. Administration of NSC689857 (5 mg/kg) also induced antidepressant-like effects in non-stressed male mice when administered three times within 24 h (24, 5, and 1 h before testing) but not when administered acutely (1 h before testing). In addition, NSC689857 and fluoxetine coadministration produced additive antidepressant-like effects in non-stressed male mice. These effects of NSC689857 were not associated with the changes in locomotor activity. Administration of NSC689857 (5 mg/kg) also attenuated depression-like behaviors in male mice induced by chronic social defeat stress, suggesting therapeutic potential of NSC689857 in depression. Overall, these results suggest that NSC689857 is capable of exerting antidepressant-like effects in both non-stressed and chronically stressed mice.

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Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis

Cited by 13 publications

References 99 publications

From diverticulosis to complicated diverticular disease: Progression of myogenic alterations and oxidative imbalance

From diverticulosis to complicated diverticular disease: Progression of myogenic alterations and oxidative imbalance

Perivascular cells function as mechano-structural sensors of vascular capillaries

NSC689857, an inhibitor of Skp2, produces antidepressant-like effects in mice

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