Abstract
Vascular connectivity between adjacent vessel beds within and between tissue compartments is essential to any successful neovascularization process. To establish new connections, growing neovessels must locate other vascular elements during angiogenesis, often crossing matrix and other tissue-associated boundaries and interfaces. How growing neovessels traverse any tissue interface, whether part of the native tissue structure or secondary to a regenerative procedure (e.g., an implant), is not known. In this study, we developed an experimental model of angiogenesis wherein growing neovessels must interact with a 3D interstitial collagen matrix interface that separates two distinct tissue compartments. Using this model, we determined that matrix interfaces act as a barrier to neovessel growth, deflecting growing neovessels parallel to the interface. Computational modeling of the neovessel/matrix biomechanical interactions at the interface demonstrated that differences in collagen fibril density near and at the interface are the likely mechanism of deflection, while fibril alignment guides deflected neovessels along the interface. Interestingly, stromal cells facilitated neovessel interface crossing during angiogenesis via a vascular endothelial growth factor (VEGF)-A dependent process. However, ubiquitous addition of VEGF-A in the absence of stromal cells did not promote interface invasion. Therefore, our findings demonstrate that vascularization of a tissue via angiogenesis involves stromal cells providing positional cues to the growing neovasculature and provides insight into how a microvasculature is organized within a tissue.
Highlights
The process of angiogenesis is fundamental to the formation of new vasculatures during development (Breier, 2000; Nunes et al, 2013), tissue repair (Ravanti and Kahari, 2000), tumorigenesis (Folkman, 1995; Grant et al, 2002), and tissue engraftment (Laschke et al, 2006)
Scanning electron microscopy of the collagen structure indicated that the fibril structure from the core, across the interface, and into the field is heterogeneous with differences in both fibril structure and density (Figures 1C,D)
Second harmonic generation imaging revealed the interface is comprised of a dense band of collagen relative to the less dense core and field regions, and circumferential fibril alignment at the interface was occasionally observed (Figures 1D–F and Supplementary Figure S7)
Summary
The process of angiogenesis is fundamental to the formation of new vasculatures during development (Breier, 2000; Nunes et al, 2013), tissue repair (Ravanti and Kahari, 2000), tumorigenesis (Folkman, 1995; Grant et al, 2002), and tissue engraftment (Laschke et al, 2006). Stromal Cells Promote Neovascular Invasion neovessels navigate through complex tissue structures and stromal compartments in the adult. A neovessel must cross a tissue interface comprised of structured matrix and cells to increase tissue vascularization or to engage with a perfused vascular unit. The latter role of the stroma as a potential barrier to neovessel growth and elongation is relevant when new vascular connections are required to form between adjacent vascular beds, whether present in neighboring tissue compartments or between two distinct tissues. Effective neovascular invasion is perhaps most relevant to the vascularization of implanted tissues. In the absence of this interface invasion, the implant/graft will become ischemic and fail
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