Regulator of calcineurin 1 mediates pathological vascular wall remodeling

Esteban, Vanesa; Méndez‐Barbero, Nerea; Jiménez-Borreguero, Luis Jesús; Roqué, Mercè; Novensá, Laura; García-Redondo, Ana B.; Salaíces, Mercedes; Vilá, Luis M.; Arbonés, María L.; Campanero, Miguel R.; Redondo, Juan Miguel

doi:10.1084/jem.20110503

Cited by 58 publications

(79 citation statements)

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“…It was recently reported that artery remodeling induced by angiotensin II infusion is prevented by inhibitors of calcineurin (48). A potential role for calcineurin in artery remodeling is interesting in the context of acid-base transport because we and others have reported that NHE1 is important for artery structure development and remodeling (10,49,50).…”

Section: Discussionmentioning

confidence: 89%

Splice Cassette II of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Interacts with Calcineurin A

Danielsen

Parker

Lee

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 89%

Splice Cassette II of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Interacts with Calcineurin A

Danielsen

Parker

Lee

et al. 2013

Journal of Biological Chemistry

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“…Interestingly, calcineurindependent expression of RCAN1.4 in other cell types has been linked to pathological vascular wall remodeling 34 and atherosclerosis progression. 35 Hence, the potential role of PMCA4 in the modulation of vascular pathologies linked to RCAN1.4 aberrant expression deserves further investigation.…”

Section: Discussionmentioning

confidence: 99%

Plasma Membrane Calcium ATPase Isoform 4 Inhibits Vascular Endothelial Growth Factor–Mediated Angiogenesis Through Interaction With Calcineurin

Baggott

Alfranca

López-Maderuelo

et al. 2014

ATVB

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Objective— Vascular endothelial growth factor (VEGF) has been identified as a crucial regulator of physiological and pathological angiogenesis. Among the intracellular signaling pathways triggered by VEGF, activation of the calcineurin/nuclear factor of activated T cells (NFAT) signaling axis has emerged as a critical mediator of angiogenic processes. We and others previously reported a novel role for the plasma membrane calcium ATPase (PMCA) as an endogenous inhibitor of the calcineurin/NFAT pathway, via interaction with calcineurin, in cardiomyocytes and breast cancer cells. However, the functional significance of the PMCA/calcineurin interaction in endothelial pathophysiology has not been addressed thus far. Approach and Results— Using in vitro and in vivo assays, we here demonstrate that the interaction between PMCA4 and calcineurin in VEGF-stimulated endothelial cells leads to downregulation of the calcineurin/NFAT pathway and to a significant reduction in the subsequent expression of the NFAT-dependent, VEGF-activated, proangiogenic genes RCAN1.4 and Cox-2 . PMCA4-dependent inhibition of calcineurin signaling translates into a reduction in endothelial cell motility and blood vessel formation that ultimately impairs in vivo angiogenesis by VEGF. Conclusions— Given the importance of the calcineurin/NFAT pathway in the regulation of pathological angiogenesis, targeted modulation of PMCA4 functionality might open novel therapeutic avenues to promote or attenuate new vessel formation in diseases that occur with angiogenesis.

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“…Lentivirus-encoding wild-type mouse Mmp17 ( Figure 6A) was injected into Mmp17 −/− mice on postnatal day 1 (P1). After confirming lentivirus-derived Mmp17 protein expression and corresponding Mmp17 mRNA levels in aortic VSMCs 7 days after injection (Online Figure VIIIA and VIIIB), 26 we analyzed early (P8) and late (8 weeks) phenotypic features ( Figure 6B). Expression of catalytically active Mmp17 from P1 restored VSMC proliferation to normal levels at P8 ( Figure 6C) and prevented aortic wall alterations in adult Mmp17 −/− mice, including diastolic pressure, density of VSMC nuclei, wall thickness in nonpressure-fixed aortas, VSMC morphology and orientation, ECM organization, and distribution of the contractility marker calponin ( Figure 6D-6H).…”

Section: Lentivirus-based Gene Therapy Rescues the Arterial Phenotypementioning

confidence: 93%

Deficiency of MMP17/MT4-MMP Proteolytic Activity Predisposes to Aortic Aneurysm in Mice

Martín-Alonso

García-Redondo

Guo

et al. 2015

Circulation Research

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A ortic aneurysm predisposes the aorta to dissection or rupture and causes 1% to 2% of deaths in developed countries.1 Thoracic aortic aneurysms and acute aortic dissections (TAADs) that affect young patients result primarily from genetic mutations. 2 The vulnerability of the aortic wall is mainly because of its poor ability to appropriately accommodate hemodynamic changes. The aortic wall, particularly in the thoracic aorta, is able to distend without requiring subsequent contraction of vascular smooth muscle cells (VSMCs) because of the elastic recoil provided by the layers of elastin lamellae.3 These mechanical properties depend on the intimate physical and mechanical connections of differentiated VSMCs with the extracellular matrix (ECM, mostly elastin, and collagen) that they produce and organize, connections that are established through force-dependent adhesion proteins (integrins), and the cytoskeleton (actin and myosin).3 During aortic development, VSMCs differentiate from neural crest and second heart field progenitors and also from mesenchymal progenitors recruited to the nascent endothelial tube; during this process, proper interaction needs to Molecular Medicine© 2015 American Heart Association, Inc. Rationale: Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries.These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome.Objective: To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology. be established between VSMCs and the ECM. 4 Detailed analysis of pulmonary artery development demonstrated that formation of the vessel wall involves the induction of successive layers of VSMCs and the invasion of the outer layers through the reorientation and radial migration of the inner ones. Methods and Results:5 Transforming growth factor (TGF)-B has been extensively studied as an inducer of VSMC maturation, and more recent studies have identified gradients of platelet-derived growth factor (PDGF)-B and other not-yet identified signals as regulators of VSMC differentiation, providing new insights into artery wall development. 5This intimate connection between VSMCs and the ECM ensures that alterations to one affect the other and can have similar effects on the overall mechanical behavior of the vessel. Thus, TAADs can be caused by mutations that affect VSMC function or that alter ECM composition and assembly.2 For example, Marfan syndrome, a genetic syndrome that predisposes to TAAD, is caused by mutations in the fibrillin-1 (FBN1) gene, which encodes an ECM protein necessary for proper elastin formation, 6 whereas in Loeys-Dietz syndrome, TGFB receptors type 1 and 2 (TGFBR1 and TGFBR2) are mutated, 7 resulting in impeded VSMC differentiation.8 Predispositi...

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Regulator of calcineurin 1 mediates pathological vascular wall remodeling

Abstract: Angiotensin-II–driven calcineurin activation and regulator of calcineurin-1 (Rcan-1) expression is required for pathological vascular remodeling in mice.

Cited by 58 publications

References 84 publications

Splice Cassette II of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Interacts with Calcineurin A

Splice Cassette II of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Interacts with Calcineurin A

Plasma Membrane Calcium ATPase Isoform 4 Inhibits Vascular Endothelial Growth Factor–Mediated Angiogenesis Through Interaction With Calcineurin

Deficiency of MMP17/MT4-MMP Proteolytic Activity Predisposes to Aortic Aneurysm in Mice

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