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Linking gene dynamics to vascular hyperplasia - Toward a predictive model of vein graft adaptation.

ABSTRACT: Reductionist approaches, where individual pieces of a process are examined in isolation, have been the mainstay of biomedical research. While these methods are effective in highly compartmentalized systems, they fail to account for the inherent plasticity and non-linearity within the signaling structure. In the current manuscript, we present the computational architecture for tracking an acute perturbation in a biologic system through a multiscale model that links gene dynamics to cell kinetics, with the overall goal of predicting tissue adaptation. Given the complexity of the genome, the problem is made tractable by clustering temporal changes in gene expression into unique patterns. These cluster elements form the core of an integrated network that serves as the driving force for the response of the biologic system. This modeling approach is illustrated using the clinical scenario of vein bypass graft adaptation. Vein segments placed in the arterial circulation for treatment of advanced occlusive disease can develop an aggressive hyperplastic response that narrows the lumen, reduces blood flow, and induces in situ thrombosis. Reducing this hyperplastic response has been a long-standing but unrealized goal of biologic researchers in the field. With repeated failures of single target therapies, the redundant response pathways are thought to be a fundamental issue preventing progress towards a solution. Using the current framework, we demonstrate how theoretical genomic manipulations can be introduced into the system to shift the adaptation to a more beneficial phenotype, where the hyperplastic response is mitigated and the risk of thrombosis reduced. Utilizing our previously published rabbit vein graft genomic data, where grafts were harvested at time points ranging from 2 hours to 28 days and under differential flow conditions, and a customized clustering algorithm, five gene clusters that differentiated the low flow (i.e., pro-hyperplastic) from high flow (i.e., anti-hyperplastic) response were identified. The current analysis advances these general associations to create a model that identifies those genes sets most likely to be of therapeutic benefit. Using this approach, we examine the range of potential opportunities for intervention via gene cluster over-expression or inhibition, delivered in isolation or combination, at the time of vein graft implantation.

SUBMITTER: Casarin S

PROVIDER: S-EPMC5708843 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Linking gene dynamics to vascular hyperplasia - Toward a predictive model of vein graft adaptation.

Casarin Stefano S Berceli Scott A SA Garbey Marc M

PloS one 20171130 11

Reductionist approaches, where individual pieces of a process are examined in isolation, have been the mainstay of biomedical research. While these methods are effective in highly compartmentalized systems, they fail to account for the inherent plasticity and non-linearity within the signaling structure. In the current manuscript, we present the computational architecture for tracking an acute perturbation in a biologic system through a multiscale model that links gene dynamics to cell kinetics, ...[more]

PMID: 29190638

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Project description:ObjectiveInflammation is a key driver of excessive neointimal hyperplasia within vein grafts. Recent work demonstrates that specialized proresolving lipid mediators biosynthesized from omega-3 polyunsaturated fatty acids, such as resolvin D1 (RvD1), actively orchestrate the process of inflammation resolution. We investigated the effects of local perivascular delivery of RvD1 in a rabbit vein graft model.MethodsIpsilateral jugular veins were implanted as carotid interposition grafts through an anastomotic cuff technique in New Zealand white rabbits (3-4 kg; N = 80). RvD1 (1 μg) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel (Sigma-Aldrich, St. Louis, Mo) or a thin bilayered poly(lactic-co-glycolic acid) (PLGA) film. No treatment (bypass only) and vehicle-loaded Pluronic gels or PLGA films served as controls. Delivery of RvD1 to venous tissue was evaluated 3 days later by liquid chromatography-tandem mass spectrometry. Total leukocyte infiltration, macrophage infiltration, and cell proliferation were evaluated by immunohistochemistry. Elastin and trichrome staining was performed on grafts harvested at 28 days after bypass to evaluate neointimal hyperplasia and vein graft remodeling.ResultsPerivascular treatments did not influence rates of graft thrombosis (23%), major wound complications (4%), or death (3%). Leukocyte (CD45) and macrophage (RAM11) infiltration was significantly reduced in the RvD1 treatment groups vs controls at 3 days (60%-72% reduction; P < .01). Cellular proliferation (Ki67 index) was also significantly lower in RvD1-treated vs control grafts at 3 days (40%-50% reduction; P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% vs bypass only (P < .001) and by 63% vs vehicle gel (P < .001). RvD1-loaded PLGA films reduced neointimal formation at 28 days by 50% vs bypass only (P < .001). RvD1 treatment was also associated with reduced collagen deposition in vein grafts at 28 days.ConclusionsLocal perivascular delivery of RvD1 attenuates vein graft hyperplasia without associated toxicity in a rabbit carotid bypass model. This effect appears to be mediated by both reduced leukocyte recruitment and decreased cell proliferation within the graft. Perivascular PLGA films may also impart protection through biomechanical scaffolding in this venous arterialization model. Our studies provide further support for the potential therapeutic role of specialized proresolving lipid mediators such as D-series resolvins in modulating vascular injury and repair.

Project description:Vein grafts, the most commonly used conduits in multi-vessel coronary artery bypass grafting surgery, have high intermediate- and long-term failure rates. The abrupt and marked increase in hemodynamic loads on the vein graft is a known contributor to failure. Recent computational modeling suggests that veins can more successfully adapt to an increase in mechanical load if the rate of loading is gradual. Applying an external wrap or support at the time of surgery is one way to reduce the transmural load, and this approach has improved performance relative to an unsupported vein graft in several animal studies. Yet, a clinical trial in humans has shown benefits and drawbacks, and mechanisms by which an external wrap affects vein graft adaptation remain unknown. This study aims to elucidate such mechanisms using a multimodal experimental and computational data collection pipeline. We quantify morphometry using magnetic resonance imaging, mechanics using biaxial testing, hemodynamics using computational fluid dynamics, structure using histology, and transcriptional changes using bulk RNA-sequencing in an ovine carotid-jugular interposition vein graft model, without and with an external biodegradable wrap that allows loads to increase gradually. We show that a biodegradable external wrap promotes luminal uniformity, physiological wall shear stress, and a consistent vein graft phenotype, namely, it prevents over-distension, over-thickening, intimal hyperplasia, and inflammation, and it preserves mechanotransduction. These mechanobiological insights into vein graft adaptation in the presence of an external support can inform computational growth and remodeling models of external support and facilitate design and manufacturing of next-generation external wrapping devices. STATEMENT OF SIGNIFICANCE: External mechanical support is emerging as a promising technology to prevent vein graft failure following coronary bypass graft surgery. While variants of this technology are currently under investigation in clinical trials, the fundamental mechanisms of adaptation remain poorly understood. We employ an ovine carotid-jugular interposition vein graft model, with and without an external biodegradable wrap to provide mechanical support, and probe vein graft adaptation using a multimodal experimental and computational data collection pipeline. We quantify morphometry using magnetic resonance imaging, mechanics using biaxial testing, fluid flow using computational fluid dynamics, vascular composition and structure using histology, and transcriptional changes using bulk RNA sequencing. We show that the wrap mitigates vein graft failure by promoting multiple adaptive mechanisms (across biological scales).

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Linking gene dynamics to vascular hyperplasia - Toward a predictive model of vein graft adaptation.

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Linking gene dynamics to vascular hyperplasia - Toward a predictive model of vein graft adaptation.

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