Central nervous system (CNS) vasculature, like the tissue is supplies, is truly unique. The distinctive features of the CNS vasculature, including an unusually dense vascular plexus and barrier properties, are stimulated during development by a mixture of bioactive ligands produced by the neural environment. In this way, the CNS builds a vascular plexus to fit its needs. Despite recent advances, many neuro-vascular cues likely remain unidentified and how endothelial cells integrate diverse neural-derived signals to ensure vascular growth and integrity is not well understood. Addressing these gaps in our knowledge will provide insight into the underlying causes of developmental neuro-vascular pathologies and potentially reveal novel therapeutic strategies to correct these defects and prevent irreversible damage to the CNS. Further, greater insight into basic mechanisms of neuro-vascular development could offer new tactics to target regenerative and pathological angiogenesis in the mature CNS. We have identified a novel role for Retinoic Acid (RA) signaling in CNS vascular development. Based on our analysis of endothelial RA signaling mutants, we hypothesize that RA ensures successful CNS vessel growth, maturation and stabilization by modulating Wnt-?-catenin signaling. We will test this hypothesis in three distinct aims.
In Aim 1, we will 1) identify a role for RA signaling in controlling brain endothelial cell and pericyte proliferation required for vascular stability and 2) determine how RA, via its receptor RAR?, inhibits Wnt-?-catenin activity in CNS endothelial cells.
In Aim 2, we will determine how transcription factor Sox17, regulated by endothelial RA and Wnt-?-catenin signaling, regulates CNS vascular growth and brain pericyte recruitment.
In Aim 3 we will elucidate the function of RA in retinal vascular development and identify a role for RA deficiency in the developmental vascular pathology retinopathy-of-prematurity. Completion of experiments in this proposal will provide new knowledge about molecular regulation of neurovascular development and will add greatly to the working model of CNS endothelial-pericyte regulation, an important framework that can be used to develop new hypothesis regarding how neurovascular pathologies develop and can ultimately be treated.

Public Health Relevance

Deficiencies in blood flow, integrity or number of blood vessels is the underlying cause or a significant component of a range of central nervous system (CNS) disorders, many of which greatly impair cognitive, sensory and motor function or are fatal. In this proposal we seek to understand how signals, produced by the CNS during development, work together to ensure blood vessels are built properly to withstand the demands of a lifetime of blood circulation. Deficiencies in neural-derived signals and the genes they regulate underlie defects in the CNS vasculature that cause disease. Elucidating the interchange of signals between CNS tissues and its vasculature is important for addressing the broader question of how CNS vascular defects occur and can be treated.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Koenig, James I
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University of Colorado Denver
Schools of Medicine
United States
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Mishra, Swati; Kelly, Kathleen K; Rumian, Nicole L et al. (2018) Retinoic Acid Is Required for Neural Stem and Progenitor Cell Proliferation in the Adult Hippocampus. Stem Cell Reports 10:1705-1720
Bonney, Stephanie; Siegenthaler, Julie A (2017) Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties. eNeuro 4:
Mishra, Swati; Choe, Youngshik; Pleasure, Samuel J et al. (2016) Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF-A pathways downstream of retinoic acid from the meninges. Dev Biol 420:148-165
Bonney, Stephanie; Harrison-Uy, Susan; Mishra, Swati et al. (2016) Diverse Functions of Retinoic Acid in Brain Vascular Development. J Neurosci 36:7786-801