Vascular guidance tunnels direct endothelial cell‐pericyte interactions and basement membrane matrix deposition

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Endothelial cell (EC) tube morphogenesis in 3D extracellular matrices is controlled by EC intracellular vacuolation and vesicular fusion leading to lumen formation and interconnection of neighboring cells to form multicellular tube networks. These latter events require proteolysis in collagen matrices by MT1‐MMP. The EC generated proteolyzed spaces, termed vascular guidance tunnels, represent a physical imprint in the matrix allowing for cellular movement and tube remodeling within these spaces in an MMP‐independent manner. Over a period of days, time‐lapse and immunofluorescence microscopy shows marked recruitment of pericytes into these vascular guidance tunnels. The creation of a 2D plane within a 3D matrix environment allows for enhanced EC‐pericyte interactions, proteolytic independent movement and pericyte proliferation. Furthermore, it is only when pericytes are present within the vascular guidance tunnels that deposition of the basement membrane components collagen type IV, laminin, nidogens 1/2, and perlecan occurs. In the absence of pericytes, ECs produce each of these components, although they are not locally deposited. Pericyte proliferation within these tunnel spaces increases the ratio of pericytes to ECs leading to basement membrane matrix deposition and EC tube stabilization.