Abstract
Objective: Angiogenesis is the growth of new vessels from pre-existing vessels and commonly associated with two modes: capillary sprouting and capillary splitting. Previous work by our laboratory suggests vascular island incorporation might be another endothelial cell dynamic involved in microvascular remodeling. Vascular islands are defined as endothelial cell segments disconnected from nearby networks, but their origin remains unclear. The objective of this study was to determine whether vascular islands associated with microvascular regression are involved in network regrowth.Methods: Mesenteric tissues were harvested from adult male Wistar rats according to the experimental groups: unstimulated, post stimulation (10 and 70 days), and 70 days post stimulation + restimulation (3 and 10 days). Stimulation was induced by mast cell degranulation via intraperitoneal injections of compound 48/80. Tissues were immunolabeled for PECAM (endothelial cells), neuron-glial antigen 2 (NG2) (pericytes), collagen IV (basement membrane), and BrdU (proliferation).Results: Percent vascular area per tissue area and length density increased by day 10 post stimulation compared to the unstimulated group. At day 70, vascular area and length density were then decreased, indicating vascular regression compared to the day 10 levels. The number of vascular islands at day 10 post stimulation was dramatically reduced compared to the unstimulated group. During regression at day 70, the number of islands increased. The disconnected endothelial cells were commonly bridged to surrounding networks by collagen IV labeling. NG2-positive pericytes were observed both along the islands and the collagen IV tracks. At 3 days post restimulation, vascular islands contained BrdU-positive cells. By day 10 post restimulation, when vascular area and length density were again increased, and the number of vascular islands was dramatically reduced.Conclusion: The results suggest that vascular islands originating during microvascular regression are capable of undergoing proliferation and incorporation into nearby networks during network regrowth.
Highlights
The design of therapies aimed at manipulating the microcirculation requires a greater understanding of the cellular dynamics involved in angiogenesis in adult tissues
The disconnected endothelial cells were commonly bridged to surrounding networks by collagen IV labeling
The results suggest that vascular islands originating during microvascular regression are capable of undergoing proliferation and incorporation into nearby networks during network regrowth
Summary
The design of therapies aimed at manipulating the microcirculation requires a greater understanding of the cellular dynamics involved in angiogenesis in adult tissues. Capillary sprouting involves the proliferation and migration of endothelial cells from an existing vessel. Work by our laboratory suggested that vascular island incorporation is a potential third endothelial cell dynamic involved in angiogenesis (Kelly-Goss et al, 2012; Stapor et al, 2013). Vascular islands are defined as endothelial cell segments disconnected from a nearby network. The study by Kelly-Goss et al identified that they are multi-cellular, containing endothelial cells and pericytes, and undergo proliferation and increased branching during angiogenesis. Stapor et al demonstrated that vascular islands are able to connect to their nearby network during angiogenesis. While these findings support a role for vascular islands in angiogenesis, their origin remains unclear.
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