Blood flow controls bone vascular function and osteogenesis.

Saravana K Ramasamy,Maria Schiller,Anne Limbourg,Massimo M Santoro,Florian P Limbourg,M Gabriele Bixel,Carlo Milia,Jaba Gamrekelashvili,Ralf H Adams,Alexander Medvinsky,Dagmar Zeuschner,Anjali P Kusumbe

doi:10.1038/ncomms13601

Abstract

While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system.

Highlights

While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood
We find that reduced blood flow and Notch activity in the bone endothelium of aged mice affects angiogenesis and osteogenesis, which is reverted by genetic approaches activating Notch in endothelial cells (ECs)
We investigated the arrangement of arteries, veins and capillaries in tibia to understand fundamental aspects of blood flow pattern in bone

Summary

Introduction

While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Skeletal blood flow and endothelial Notch activity are reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Type H endothelial cells (ECs) secrete osteogenic factors and maintain Osterix þ osteoprogenitors, but this crucial vessel subtype declined in ageing animals, which was accompanied by reduced osteoprogenitor numbers and loss of bone mass[8,9]. We find that reduced blood flow and Notch activity in the bone endothelium of aged mice affects angiogenesis and osteogenesis, which is reverted by genetic approaches activating Notch in ECs. The sum of our work highlights central roles of Notch signalling in bone endothelium and its regulation by blood flow, which is relevant for age-related bone loss and, potentially, for therapeutic approaches aiming at the maintenance or restoration of bone mass

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Conclusion