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Molecular Control of Capillary Tube Morphogenesis and Maturation Through Endothelial Cell-Pericyte Interactions: Regulation by Small GTPase-Mediated Signaling, Kinase Cascades, Extracellular Matrix Remodeling, and Defined Growth Factors

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Biophysical Regulation of Vascular Differentiation and Assembly

Part of the book series: Biological and Medical Physics, Biomedical Engineering ((BIOMEDICAL))

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Abstract

Studies over many years reveal a critical role for extracellular matrices, matrix metalloproteinases, key small GTPases, and defined growth factors in the molecular control of vascular tube morphogenesis and stabilization in three-dimensional (3D) tissue environments. Key interactions involve endothelial cells (ECs) and pericytes which co-assemble to affect vessel formation, remodeling and stabilization events during development and postnatal life. The EC tube formation process results in the creation of networks of proteolytically generated vascular guidance tunnels. These tunnels are physical matrix spaces that regulate vascular tube remodeling and represent matrix conduits into which pericytes are recruited, to allow dynamic and polarized cell-cell interactions with ECs. EC-pericyte interactions regulate vascular basement membrane matrix assembly, a necessary step for endothelial tube maturation and stabilization. ECs form tube networks and tunnels in 3D extracellular matrices in a manner dependent on integrins; membrane-type metalloproteinases; small GTPases including Cdc42, Rac isoforms, k-Ras, and Rap1b; and key downstream effectors of these GTPases. In addition, human EC tubulogenesis requires a defined five-growth factor combination including stem cell factor (SCF), interleukin-3 (IL-3), stromal-derived factor-1 alpha (SDF-1α), fibroblast growth factor-2 (FGF-2), and insulin (Factors). These Factors are necessary to integrate signal transduction cascades to form human EC tube networks and attract pericytes [through EC-derived platelet-derived growth factor (PDGF)-BB and heparin-binding epidermal growth factor (HB-EGF)] to control vessel maturation events.

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Acknowledgments

This work was supported by NIH grants HL126518, HL128584, and HL136139 to G.E. Davis.

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  1. Department of Molecular Pharmacology and Physiology, University of South Florida School of Medicine, Tampa, FL, USA

    George E. Davis

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Correspondence to George E. Davis .

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  1. Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Sciences–Oncology Center and Institute for NanoBioTechnology, Baltimore, MD, USA

    Sharon Gerecht

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Davis, G.E. (2018). Molecular Control of Capillary Tube Morphogenesis and Maturation Through Endothelial Cell-Pericyte Interactions: Regulation by Small GTPase-Mediated Signaling, Kinase Cascades, Extracellular Matrix Remodeling, and Defined Growth Factors. In: Gerecht, S. (eds) Biophysical Regulation of Vascular Differentiation and Assembly. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-99319-5_1

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