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      JAGGED-NOTCH3 signaling in vascular remodeling in pulmonary arterial hypertension

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          Abstract

          Within the pulmonary arterial tree, the NOTCH3 pathway is crucial in controlling vascular smooth muscle cell proliferation and maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension (PAH) is a fatal disease without cure, characterized by elevated pulmonary vascular resistance due to vascular smooth muscle cell proliferation in precapillary arteries, perivascular inflammation, and asymmetric neointimal hyperplasia. Here, we show that human PAH is characterized by overexpression of the NOTCH ligand JAGGED-1 (JAG-1) in small pulmonary artery smooth muscle cells and that JAG-1 selectively controls NOTCH3 signaling and cellular proliferation in an autocrine fashion. In contrast, the NOTCH ligand DELTA-LIKE 4 is minimally expressed in small pulmonary artery smooth muscle cells from individuals with PAH, inhibits NOTCH3 cleavage and signaling, and retards vascular smooth muscle cell proliferation. A new monoclonal antibody for the treatment of PAH, which blocks JAG-1 cis- and trans-induced cleavage of the NOTCH3 receptor in the pulmonary vasculature, was developed. Inhibition of JAG-1–induced NOTCH3 signaling in the lung reverses clinical and pathologic pulmonary hypertension in two rodent models of disease, without toxic side effects associated with nonspecific NOTCH inhibitors. Our data suggest opposing roles of NOTCH ligands in the pulmonary vasculature in pulmonary hypertension. We propose that selectively targeting JAG-1 activation of NOTCH3 may be an effective, safe strategy to treat PAH.

          Abstract

          Pulmonary arterial hypertension can be reversed in rodents using a monoclonal antibody that targets the selective activation of NOTCH3 by JAGGED-1.

          Reversing pulmonary vascular remodeling

          Vascular smooth muscle cells (vSMCs) proliferate and alter the architecture of pulmonary arteries in pulmonary arterial hypertension (PAH), contributing to elevated pulmonary vascular resistance. Here, Zhang et al. investigated the role of NOTCH3 signaling in PAH. JAGGED-1, a ligand of NOTCH3, was elevated in vSMCs from humans with PAH and mice with PH, and JAGGED-1 promoted cell proliferation in an autocrine manner. Treating mouse and rat models of PH with the anti-NOTCH3 antibody Ab 28042, which inhibits JAGGED-1–NOTCH3 signaling, reversed PH. The authors did not observe signs of local or systemic toxicity, which suggests that blocking JAGGED-1–NOTCH3 interactions could be a promising therapeutic approach for patients with PAH.

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          Most cited references49

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          Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension.

          This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries.
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            Notch3 is required for arterial identity and maturation of vascular smooth muscle cells.

            Formation of a fully functional artery proceeds through a multistep process. Here we show that Notch3 is required to generate functional arteries in mice by regulating arterial differentiation and maturation of vascular smooth muscle cells (vSMC). In adult Notch3-/- mice distal arteries exhibit structural defects and arterial myogenic responses are defective. The postnatal maturation stage of vSMC is deficient in Notch3-/- mice. We further show that Notch3 is required for arterial specification of vSMC but not of endothelial cells. Our data reveal Notch3 to be the first cell-autonomous regulator of arterial differentiation and maturation of vSMC.
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              Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.

              The self-renewing epithelium of the small intestine is ordered into stem/progenitor crypt compartments and differentiated villus compartments. Recent evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt-villus axis. Here we show a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J. We obtained a similar phenotype by blocking the Notch cascade with a gamma-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumour suppressor gene. Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. Our data indicate that gamma-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.
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                Author and article information

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                Journal
                Science Translational Medicine
                Sci. Transl. Med.
                American Association for the Advancement of Science (AAAS)
                1946-6234
                1946-6242
                May 04 2022
                May 04 2022
                : 14
                : 643
                Affiliations
                [1 ]Division of Cardiothoracic Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
                [2 ]Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
                Article
                10.1126/scitranslmed.abl5471
                35507674
                ec1c9fb5-f865-46c5-aedf-84112e0d1932
                © 2022
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