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1.
bioRxiv ; 2023 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-37873248

RESUMO

Atherosclerosis is a chronic inflammatory disease which is driven in part by the aberrant trans -differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects. Using SMC fate mapping in an advanced atherosclerotic lesion model, colchicine induced plaque regression by converting pathogenic SMC-derived macrophage-like and osteoblast-like cells into protective myofibroblast-like cells which thickened, and thereby stabilized, the fibrous cap. This was dependent on Notch3 signaling in SMC-derived plaque cells. These findings may help explain the success of colchicine in clinical trials relative to other anti-inflammatory drugs. Thus, we demonstrate the potential of regulating SMC phenotype in advanced plaque regression through Notch3 signaling, in addition to the canonical anti-inflammatory actions of drugs to treat atherosclerosis.

2.
Cells ; 10(3)2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800271

RESUMO

Mural cells collectively refer to the smooth muscle cells and pericytes of the vasculature. This heterogenous population of cells play a crucial role in the regulation of blood pressure, distribution, and the structural integrity of the vascular wall. As such, dysfunction of mural cells can lead to the pathogenesis and progression of a number of diseases pertaining to the vascular system. Cardiovascular diseases, particularly atherosclerosis, are perhaps the most well-described mural cell-centric case. For instance, atherosclerotic plaques are most often described as being composed of a proliferative smooth muscle cap accompanied by a necrotic core. More recently, the role of dysfunctional mural cells in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, is being recognized. In this review, we begin with an exploration of the mechanisms underlying atherosclerosis and neurodegenerative diseases, such as mural cell plasticity. Next, we highlight a selection of signaling pathways (PDGF, Notch and inflammatory signaling) that are conserved across both diseases. We propose that conserved mural cell signaling mechanisms can be exploited for the identification or development of dual-pronged therapeutics that impart both cardio- and neuroprotective qualities.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Miócitos de Músculo Liso/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Pericitos/efeitos dos fármacos , Placa Aterosclerótica/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Cardiotônicos/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Pericitos/metabolismo , Pericitos/patologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais
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