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      NOTCH3 as a modulator of vascular disease: a target in elastin deficiency and arterial pathologies

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      1 , 2 , 2 ,
      The Journal of Clinical Investigation
      American Society for Clinical Investigation

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          Abstract

          During blood vessel disease, vascular smooth muscle cell (VSMC) expansion and interaction with the matrix trigger changes in gene expression and phenotype. In this issue of the JCI, Dave et al. discover a signaling network that drives VSMC expansion and vascular obstruction caused by elastin insufficiency. Using a combination of gene-targeted mice, tissues and cells from patients with Williams-Beuren syndrome, and targeting of elastin in human VSMCs, the authors identified VSMC-derived NOTCH3 signaling as a critical mediator of aortic hypermuscularization and loss of vascular patency. NOTCH3-specific therapies or therapies that target downstream molecular pathways may provide opportunities to minimize VSMC growth and treat cardiovascular disease with minimal side effects.

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          Most cited references24

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          Developmental basis of vascular smooth muscle diversity.

          The origins of vascular smooth muscle are far more diverse than previously thought. Lineage mapping studies show that the segmental organization of early vertebrate embryos leaves footprints on the adult vascular system in the form of a mosaic pattern of different smooth muscle types. Moreover, evolutionarily conserved tissue forming pathways produce vascular smooth muscle from a variety of unanticipated sources. A closer look at the diversity of smooth muscle origins in vascular development provides new perspectives about how blood vessels differ from one another and why they respond in disparate ways to common risk factors associated with vascular disease. The origins of vascular smooth muscle are far more diverse than previously thought. A closer look at the diversity of smooth muscle origins in vascular development provides new perspectives about how blood vessels differ from one another and why they respond in disparate ways to common risk factors associated with vascular disease.
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            Adipocyte extracellular matrix composition, dynamics and role in obesity

            The central role of the adipose tissue in lipid metabolism places specific demands on the cell structure of adipocytes. The protein composition and dynamics of the extracellular matrix (ECM) is of crucial importance for the functioning of those cells. Adipogenesis is a bi-phasic process in which the ECM develops from a fibrillar to a laminar structure as cells move from the commitment phase to the growth phase characterized by storage of vast amounts of triglycerides. Mature adipocytes appear to spend a lot of energy on the maintenance of the ECM. ECM remodeling is mediated by a balanced complement of constructive and destructive enzymes together with their enhancers and inhibitors. ECM remodeling is an energy costing process regulated by insulin, by the energy metabolism, and by mechanical forces. In the obese, overgrowth of adipocytes may lead to instability of the ECM, possibly mediated by hypoxia.
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              Cadasil.

              Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.
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                Author and article information

                Contributors
                Journal
                J Clin Invest
                J Clin Invest
                J Clin Invest
                The Journal of Clinical Investigation
                American Society for Clinical Investigation
                0021-9738
                1558-8238
                1 March 2022
                1 March 2022
                1 March 2022
                1 March 2022
                : 132
                : 5
                : e157007
                Affiliations
                [1 ]Maine Medical Partners Vascular Surgery and
                [2 ]Maine Medical Center Research Institute, MaineHealth, Scarborough, Maine, USA.
                Author notes
                Address correspondence to: Lucy Liaw, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074, USA. Phone: 207.396.8142; Email: Lucy.Liaw@ 123456mainehealth.org .
                Author information
                http://orcid.org/0000-0003-3341-0156
                Article
                157007
                10.1172/JCI157007
                8884893
                35229725
                2f665703-797e-4fd2-a88f-b719b6d22d53
                © 2022 Malka et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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