Grant: Discovery Grants Program - Individual

Embryonic angiogenesis has become dogmatic in vascular biology, but our understanding of cerebrovascular maturation after birth is scant. In the mature brain, the relationship between neuronal and vascular cells ensures a functional matching whereby neural activity regulates blood flow. The anatomical substrate of this neurovascular coupling (NVC) is the neurovascular unit (NVU), a structure in which blood vessels, neurons and astrocytes cooperate. However, NVC is functional only a few weeks after birth. Hence, the postnatal brain must rely on alternative mechanisms to satisfy demands imposed by its rapid expansion. During my post-doctoral training, I partly clarified this dichotomy, by demonstrating that neural activity promotes the growth of brain blood vessels during postnatal month. Building on this discovery, my lab now investigates the underpinnings of proper brain angiogenesis after birth, focussing on interactions between astrocytes and blood vessels.Serving as bridges between neurons and the vasculature, astrocytes express neurotransmitter receptors and send specialized extensions (endfeet) around blood vessels. Astrocytes have the ability to release of vasoactive messengers, to participate in the regulation of vascular diameter in the mature NVU, but they also release pro-angiogenic factors (e.g. vascular endothelial growth factor). Despite a wealth of knowledge on astrocytes, and while it is recognized that they mature after birth, little is known about i) their stepwise recruitment to the NVU, ii) the developmental schedule that determines synthesis of astrocyte-derived proangiogenic molecules, and iii) their contribution to brain angiogenesis during early postnatal development. We propose to characterize the time course of astroglio-vascular maturation in the mouse cerebral cortex during the first postnatal month. Using genetically-engineered mice, we will first characterize and quantify the maturation of astrocytes around blood vessels and their recruitment to the NVU. Then, the time course of astrocyte maturation will be resolved at the gene level, using advanced in situ molecular methods to assess expression of genes involved in the regulation of angiogenesis by astrocytes. In parallel, genetic tools will be used to modulate the secretion of pro-angiogenic factors by astrocytes during early postnatal development, helping us refine our hypothesis that astrocytes fine tune cerebrovascular patterning in that period. We trust that discoveries made throughout this research program will further our understanding of brain maturation.