Investigating the Patterns of Vascular Remodelling in the Healthy Adult Mouse Cortex

Abstract

Angiogenesis (the sprouting of new blood vessels from pre-existing ones) is a process that occurs naturally during many physiological and pathological processes. Given that the cerebral vasculature requires tight regulation of homeostatic environments, too much, or too little angiogenesis can severely impact brain function and maintenance. The vast majority of what we know about physiological angiogenesis (particularly in the brain) centers on early embryonic and early postnatal developmental stages where this process is driven by hypoxic signals from un-perfused tissue to develop and expand the vascular network. Once an organism reaches adulthood, the vasculature is still required to sustain the incredibly high metabolic demands of neuronal functioning; however, it remains unclear to what extent the capacity to grow new blood vessels is maintained in the healthy and stable adult vascular network. Previous work from our lab has shown that even in the healthy adult mouse cortex, spontaneous obstructions to capillaries occur on a regular basis. While the vast interconnectedness of the capillary network may be able to adapt to a few lost capillaries, the additive challenge of pruned vessels throughout the lifespan can pose a significant risk to homeostatic efforts. A quantitative analysis of the rates at which vessel density is lost naturally with age across various brain regions found that while many areas experience a significant decrease in vascular density, some areas remain resilient to significant loss. In this thesis I explore the possibility that angiogenesis compensates in a regionally dependent manner to prevent significant vessel density loss. Our results show that while there are no regional differences in the pruning rate of capillaries, angiogenesis is significantly elevated in a graded manner across the cortical surface, with ample evidence of growth of microvessels over lateral-posterior regions. On the contrary, evidence of vessel sprouting along medial-anterior regions is extremely rare. Further probing into molecular mechanisms driving adult angiogenesis, I found that it is not upregulation of pro-angiogenic factors driving regional heterogeneity, but rather an upregulation of pro-stabilizing molecules in medial regions of the cortex that put the brakes on the angiogenic switch. Our data provides concrete evidence that angiogenesis is necessary for the maintenance of vascular systems in the healthy adult mouse brain.