Harnessing systems biology approaches to engineer functional microvascular networks

Abstract

Microvascular remodeling is a complex process that includes many cell types and molecular signals. Despite a continued growth in the understanding of signaling pathways involved in the formation and maturation of new blood vessels, approximately half of all compounds entering clinical trials will fail, resulting in the loss of much time, money, and resources. Most pro-angiogenic clinical trials to date have focused on increasing neovascularization via the delivery of a single growth factor or gene. Alternatively, a focus on the concerted regulation of whole networks of genes may lead to greater insight into the underlying physiology since the coordinated response is greater than the sum of its parts. Systems biology offers a comprehensive network view of the processes of angiogenesis and arteriogenesis that might enable the prediction of drug targets and whether or not activation of the targets elicits the desired outcome. Systems biology integrates complex biological data from a variety of experimental sources (-omics) and analyzes how the interactions of the system components can give rise to the function and behavior of that system. This review focuses on how systems biology approaches have been applied to microvascular growth and remodeling, and how network analysis tools can be utilized to aid novel pro-angiogenic drug discovery.

FIG. 1.

(A) Sprouting: Released growth factors stimulate the release of enzymes that degrade the basement membrane as well as metalloproteinases that digest the extracellular matrix (ECM). Endothelial cells begin to form a migration column, proliferating toward the angiogenic gradient. Degraded ECM fragments act as haptotactic signals and further encourage cell migration. (B) Maturation: Metalloproteinases continue to degrade the ECM to allow for pericyte migration, and platelet-derived growth factor, transforming growth factor-β, and angiopoeitin signaling attract pericytes to new vessels. Once surrounding the vessel, pericytes secrete new matrix, reduce vessel permeability, and induce endothelial quiescence. (C) Intracellular: Intracellular signaling including angiopoietins and growth factors stimulate actin F-actin activity within the cell, allowing it to probe its environment, expand toward a gradient, contract, and ultimately move forward. Color images available online at www.liebertonline.com/ten.

FIG. 2.

Systems biology approaches to engineer microvascular networks aid pro-angiogenic drug discovery. Bottom-up approaches focus on collecting and accumulating empirical data about the system and then incorporating these data into a larger, more unified model that explains emergent behaviors and properties. Top-down approaches are data-driven and focus on network level integration to identify novel interactions or mechanisms. Experimental validation of the models and appropriate refinement and iteration are critical. The ultimate goal is to combine top-down and bottom-up approaches to create a unified model of the entire biological system of interest spanning different spatial and temporal scales. Color images available online at www.liebertonline.com/ten.

FIG. 3.

Network analysis tools. Microarray data from a drug of unknown mechanism can be analyzed using a compendium analysis approach (Pathways Analysis, shown on right) or a genomic-mapping approach (Connectivity Map Analysis, shown on left). Both top-down approaches rely on literature-derived knowledge bases that are manually curated and contain known genetic signatures and signaling networks. The unknown data are mapped against data from drugs with known mechanisms to identify areas of overlap, thereby indicating similarity in drug mechanism. Color images available online at www.liebertonline.com/ten.