Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis

Misra, Ashish; Sheikh, Abdul Q.; Kumar, Abhishek; Luo, Jiesi; Zhang, Jiasheng; Hinton, Robert B.; Smoot, Leslie; Kaplan, Paige; Urban, Zsolt; Qyang, Yibing; Tellides, George; Greif, Daniel M.

doi:10.1084/jem.20150688

Cited by 46 publications

(47 citation statements)

References 48 publications

(76 reference statements)

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“…Induction of Col8a1 and Col11a1 transcripts, previously associated with vascular remodeling [30,31], is perhaps readily detectable with a global analytical technique due to low basal expression. Altered expression of particular collagens may impact the transduction of mechanical stimuli from ECM to SMCs and result in disordered growth of the aorta in keeping with recent observations that integrin signaling is necessary for luminal stenosis in Eln −/− mice [32]. …”

Section: Discussionsupporting

confidence: 66%

Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency

Jiao

Korneva

et al. 2017

ATVB

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Objective Williams syndrome (WS) is characterized by obstructive aortopathy attributable to heterozygous loss of ELN, the gene encoding elastin. Lesions are thought to result primarily from excessive smooth muscle cell (SMC) proliferation and consequent medial expansion, although an initially smaller caliber and increased stiffness of the aorta may contribute to luminal narrowing. The relative contributions of such abnormalities to the obstructive phenotype had not been defined. Approach and Results We quantified determinants of luminal stenosis in thoracic aortas of Eln−/− mice incompletely rescued by human ELN. Moderate obstruction was largely due to deficient circumferential growth, most prominently of ascending segments, despite increased axial growth. Medial thickening was evident in these smaller diameter elastin-deficient aortas, with medial area similar to that of larger diameter control aortas. There was no difference in cross-sectional SMC number between mutant and wild-type genotypes at multiple stages of postnatal development. Decreased elastin content was associated with medial fibrosis and reduced aortic distensibility due to increased structural stiffness but preserved material stiffness. Elastin-deficient SMCs exhibited greater contractile-to-proliferative phenotypic modulation in vitro than in vivo. We confirmed increased medial collagen without evidence of increased medial area or SMC number in a small ascending aorta with thickened media of a WS subject. Conclusions Deficient circumferential growth is the predominant mechanism for moderate obstructive aortic disease resulting from partial elastin deficiency. Our findings suggest that diverse aortic manifestations in WS result from graded elastin content, and SMC hyperplasia causing medial expansion may require additional elastin loss superimposed on ELN haploinsufficiency.

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Section: Discussionsupporting

confidence: 66%

Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency

Jiao

Korneva

et al. 2017

ATVB

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“…Another is that mTOR triggers polymerization of F-actin, which promotes phosphorylation of focal adhesion proteins or activates integrins via IRS-1 [27–29]. The ability of mTOR inhibitors to modulate mechanoresponses in SMCs may relate to its beneficial effects on pathological aortic remodeling and reinforce the concepts that vascular cell activation and integrin-mediated mechanotransduction play important roles in elastin aortopathy [30,31]. Additionally, mTOR inhibition increased contractile protein expression in differentiated SMCs in vivo, though to a lesser extent than previously reported for de-differentiated cultured SMCs [28] and aortas with loss of SMC differentiation due to disruption of TGF-β signaling [32,33].…”

Section: Discussionmentioning

confidence: 99%

mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice

Jiao

et al. 2017

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Objective Elastin deficiency due to heterozygous loss of an ELN allele in Williams syndrome causes obstructive aortopathy characterized by medial thickening and fibrosis and consequent aortic stiffening. Previous work in Eln-null mice with a severe arterial phenotype showed that inhibition of mechanistic target of rapamycin (mTOR), a key regulator of cell growth, lessened the aortic obstruction but did not prevent early postnatal death. We investigated effects of mTOR inhibition in Eln-null mice partially rescued by human ELN that manifest a less severe arterial phenotype and survive long-term. Approach and Results Thoracic aortas of neonatal and juvenile mice with graded elastin deficiency exhibited increased signaling through both mTOR complex 1 and complex 2. Despite lower predicted wall stress, there was increased phosphorylation of focal adhesion kinase, suggestive of greater integrin activation, and increased transforming growth factor-β signaling mediators, associated with increased collagen expression. Pharmacologic blockade of mTOR by rapalogs did not improve luminal stenosis, but reduced mechanosignaling (in delayed fashion following mTOR complex 1 inhibition), medial collagen accumulation, and stiffening of the aorta. Rapalog administration also retarded somatic growth, however, and precipitated neonatal deaths. Complementary, less toxic strategies to inhibit mTOR via altered growth factor and nutrient responses were not effective. Conclusions In addition to previously demonstrated therapeutic benefits of rapalogs decreasing smooth muscle cell proliferation in the absence of elastin, we find that rapalogs also prevent aortic fibrosis and stiffening attributable to partial elastin deficiency. Our findings suggest that mTOR-sensitive perturbation of smooth muscle cell mechanosensing contributes to elastin aortopathy.

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“…“Premature stop codons in ELN may lead to nonsense-mediated mRNA decay, and thereby decreased levels of ELN and thus result in functional haploinsufficiency as it has been described for Williams syndrome.” 9,10 . Reduced elastin availability during vascular maturation results in increased cell proliferation 11 , as a result of excessive integrin β3 signaling 12 .…”

Section: Discussionmentioning

confidence: 99%

Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm

Jelsig

Urban

Hucthagowder

et al. 2017

European Journal of Medical Genetics

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Pathogenic germline mutations in ELN can be detected in patients with supravalvular aortic stenosis. The mutation might occur de novo or be inherited following an autosomal dominant pattern of inheritance. In this report we describe a three-generation family suffering from supravalvular aortic stenosis, various other arterial stenoses, sudden death, and intracranial aneurysms. A frameshift mutation in exon 12, not described before, was detected in the affected family members. This report emphasises the importance of family history, genetic counselling, and demonstrates the great variability in the phenotype within a single SVAS family.

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Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis

Abstract: Misra et al. elucidate the origin of smooth muscle cells involved in supravalvular aortic stenosis and identify the integrin β3 pathway as a therapeutic target in this disease.

Cited by 46 publications

References 48 publications

Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency

Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency

mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice

Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm

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