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Impaired integrin ?3 delays endothelial cell regeneration and contributes to arteriovenous graft failure in mice.

ABSTRACT: Neointima formation is associated with stenosis and subsequent thrombosis in arteriovenous grafts (AVGs). A role of integrin ?3 in the neointima formation of AVGs remains poorly understood.In integrin ?3(-/-) mice, we found significantly accelerated occlusion of AVGs compared with the wild-type mice. This is caused by the development of neointima and lack of endothelial regeneration. The latter is a direct consequence of impaired functions of circulating angiogenic cells (CACs) and platelets in integrin ?3(-/-) mice. Evidence suggests the involvement of platelet regulating CAC homing to and differentiation at graft sites via transforming growth factor-?1 and Notch signaling pathway. First, CACs deficient of integrin ?3 impaired adhesion activity toward exposed subendothelium. Second, platelets from integrin ?3(-/-) mice failed to sufficiently stimulate CACs to differentiate into mature endothelial cells. Finally, we found that transforming growth factor-?1 level was increased in platelets from integrin ?3(-/-) mice and resulted in enhanced Notch1 activation in CACs in AVGs. These results demonstrate that integrin ?3 is critical for endothelial cell homing and differentiation. The increased transforming growth factor-?1 and Notch1 signaling mediates integrin ?3(-/-)-induced AVG occlusion. This accelerated occlusion of AVGs was reversed in integrin ?3(-/-) mice transplanted with the bone marrow from wild-type mice.Our results suggest that boosting integrin ?3 function in the endothelial cells and platelets could prevent neointima and thrombosis in AVGs.

SUBMITTER: Liang M

PROVIDER: S-EPMC4671198 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Impaired integrin β3 delays endothelial cell regeneration and contributes to arteriovenous graft failure in mice.

Liang Ming M Wang Yun Y Liang Anlin A Dong Jin-Fei JF Du Jie J Cheng Jizhong J

Arteriosclerosis, thrombosis, and vascular biology 20150122 3

<h4>Objective</h4>Neointima formation is associated with stenosis and subsequent thrombosis in arteriovenous grafts (AVGs). A role of integrin β3 in the neointima formation of AVGs remains poorly understood.<h4>Approach and results</h4>In integrin β3(-/-) mice, we found significantly accelerated occlusion of AVGs compared with the wild-type mice. This is caused by the development of neointima and lack of endothelial regeneration. The latter is a direct consequence of impaired functions of circul ...[more]

PMID: 25614287

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Project description:AimsIt is well-established that endothelial dysfunction promotes activation of vascular smooth muscle cell (VSMC). Whether decreased accumulation of VSMCs affects endothelial regeneration and functions in arteriovenous graft (AVG) remodelling has not been studied. We sought to identify mechanisms by which the Notch ligand, Jagged1, in VSMCs regulates endothelial cell (EC) functions in AVGs.Methods and resultsAVGs were created in transgenic mice bearing VSMC-specific knockout (KO) or overexpression of Jagged1. VSMC migration, EC regeneration, and its barrier functions as well as AVG remodelling were evaluated. Jagged1 expression was induced in VSMCs of neointima in the AVGs. Jagged1 KO in VSMCs inhibited the accumulation of extracellular matrix as well as VSMC migration. Fewer α-SMA-positive VSMCs were found in AVGs created in VSMC-specific Jagged1 KO mice (VSMCJagged1 KO mice) vs. in WT mice. Decreased VSMCs in AVGs were associated with deterioration of EC functions. In AVGs created in transgenic mice bearing Jagged1 KO in VSMCs exhibited delayed EC regeneration and impaired EC barrier function. Barrier dysfunction of ECs increased inflammatory cell infiltration and dysregulation of AVG remodelling and arterialization. The increased expression of IL-1β in macrophages was associated with expression of adhesion markers in ECs in AVGs created in VSMCJagged1 KO mice. In contrast, AVGs created in mice with overexpression of Jagged1 in VSMCs exhibited improved EC regeneration plus decreased macrophage infiltration. This led to AVG remodelling and arterialization. In co-cultures of ECs and VSMCs, Jagged1 deficiency in VSMCs suppressed N-cadherin and integrin β3 expression in ECs. Inhibition of integrin β3 activation delayed EC spreading and migration. Notably, Jagged1 overexpression in VSMCs or treatment with recombinant Jagged1 stimulated the expression of N-cadherin and integrin β3 in ECs. Jagged1-induced responses were blocked by inhibition of Notch signalling.ConclusionsJagged1 expression in VSMCs maintains EC barrier functions and blocks infiltration of macrophages. These responses promote remodelling and arterialization of AVGs.

Project description:ImportanceEndothelial morphometric measures have potential value in predicting graft failure after penetrating keratoplasty.ObjectiveTo determine whether preoperative and/or postoperative central morphometric measures (endothelial cell density [ECD], coefficient of variation [CV], and percentage of hexagonality [HEX]) and their postoperative changes are predictive of graft failure caused by endothelial decompensation after penetrating keratoplasty to treat a moderate-risk condition, principally Fuchs dystrophy or pseudophakic corneal edema.DesignIn a subset of Cornea Donor Study participants with graft failure, a central reading center determined preoperative and postoperative ECD, CV, and HEX from available central endothelial specular images.SettingCornea Image Analysis Reading Center of the Specular Microscopy Ancillary Study.ParticipantsEighteen patients with graft failure due to endothelial decompensation and 54 individuals matched for most donor and recipient measures at baseline whose grafts did not fail.Main outcome measureChange in ECD, CV, and HEX values.ResultsPreoperative ECD was not associated with graft failure (P = .43); however, a lower ECD at 6 months was predictive of subsequent failure (P = .004). Coefficient of variation at 6 months was not associated with graft failure in univariate (P = .91) or multivariate (P = .79) analyses. We found a suggestive trend of higher graft failure with lower HEX values at 6 months (P = .02) but not at the established statistical significance (P < .01). The most recent CV or HEX values, as time-dependent variables, were not associated with graft failure (P = .26 and P = .81, respectively). Endothelial cell density values decreased during follow-up, whereas CV and HEX appear to fluctuate without an apparent trend.Conclusions and relevanceEndothelial cell density at 6 months after penetrating keratoplasty is predictive of graft failure, whereas CV and HEX appear to fluctuate postoperatively, possibly indicating an unstable endothelial population in clear and failing grafts.Trial registrationclinicaltrials.gov Identifier: NCT00006411.

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Impaired integrin ?3 delays endothelial cell regeneration and contributes to arteriovenous graft failure in mice.

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Impaired integrin β3 delays endothelial cell regeneration and contributes to arteriovenous graft failure in mice.

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