The pericyte microenvironment during vascular development

Abstract

Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.

Keywords: endothelial cells; pericytes; vascular morphogenesis.

Figure 1

Confocal image of a sprouting endothelial cell labeled for platelet-endothelial cell adhesion molecule-1 (PECAM-1; A and green in D, indicated by light green arrows) with an adjacent pericyte labeled for platelet-derived growth factor receptor-β (PDGFRβ; B and red in D, indicated by pink arrows) extending from a microvessel in the adult mouse brain. Cell nuclei are labeled with DAPI (C, and blue in D). The pericyte appears to engage the sprouting endothelial tip cell from the base of the filopodial extensions, along the length of the sprout and the parent vessel. Scale bar, 10 microns.

Figure 2

Time-lapse images of a sprouting endothelial cell visualized by eGFP expression from the Flk-1 promoter (left column, and green in right column) and an associated pericyte expressing the fluorescent reporter DsRed from the Ng2/Cspg4 promoter (middle column, and red in the right column) in an ex vivo model of vessel formation in the developing back skin from embryonic day 14.5 mice. Light green arrowheads indicate the apparent front of the endothelial tip cell, and pink arrowheads indicate the apparent leading edge of the associated pericyte. Time in the upper left corner of the left column indicates hours and minutes as hh:mm. Scale bar, 10 microns. Non-consecutive images were taken from the time-lapse sequence provided in Supplemental Movie 1. See Darden et al. Angiogenesis 2019 [64] for full experimental details and animal use certifications.

Figure 3

Schematic illustrating the interactions between a sprouting endothelial cell (EC, green) and an associated pericyte (PC, orange) during angiogenic remodeling. (A) Pericyte recruitment and retention factors (yellow) are secreted by endothelial tip cells to maintain pericyte coverage during vessel formation, while endothelial cell-derived extracellular matrix (ECM) proteins are also deposited (purple). (B) As pericytes establish coverage along endothelial sprouts, they secrete additional ECM components (brown) adjacent to the vessel wall to form the vascular basement membrane supporting cell migration as well as vessel stability.