The long-term goal of this study is to understand molecular mechanisms of intercellular signaling by which neural cells especially various glial cell types regulate pre- and postnatal brain angiogenesis, and coordinate the development of the neurovascular unit. Proper vascular development is critical to normal brain function and defects in this process are linked to many neurological diseases including stroke, epilepsy, and neurodegeneration. Many of the same pathways that regulate vessel development also regulate vascular integrity and function in the adult brain and need to be re-activated for vascular recovery following disease. In addition, blood brain barrier (BBB) is a major obstacle to central nervous system (CNS) delivery of pharmaceuticals for disease treatment. Thus, a better understanding of brain angiogenesis and BBB development is crucial to finding better treatments for a wide array of human diseases. To this end, we propose to focus on interactions between neural and vascular cells, since these interactions are responsible for many of the unique properties of the brain vasculature. We hypothesize that neural cells especially glia play a key role in both pre- and postnatal brain angiogenesis. In support, our preliminary data show that ablation of neural progenitors from the embryonic cortex results in vessel regression and cerebral hemorrhage. We also find that ablation of glia from the early postnatal brain disrupts vessel network elaboration and maturation. These findings therefore provide unique opportunities for better understanding molecular mechanisms that regulate vessel development throughout corticogenesis. To this end, we will: 1) Determine the signaling pathway(s) by which neural cells regulate embryonic brain vessel stabilization;2) Determine intracellular mechanisms by which brain endothelial cells regulate vessel stabilization;3) Determine signaling mechanisms by which glia regulate vessel development in the postnatal brain. Through these efforts, we will likely reveal novel molecular mechanisms by which the distinct steps of brain angiogenesis are regulated, providing new insights into the signaling pathways that need to be coordinately re-activated for vascular recovery in disease treatment. We will also likely substantially elucidate the gene expression program by which brain endothelial cells regulate vessel stabilization, and provide potential molecular targets for pharmaceutical intervention in relevant diseases.

Public Health Relevance

Close coordination between neural especially glial and vascular cells is critical to normal brain development and function. Failure of this process is associated with a large number of neurological diseases, including stroke, epilepsy, and neurodegeneration. A better understanding of molecular mechanisms by which neural (especially glial) cells regulate vessel development in the pre- and postnatal brain will thus facilitate the search for better treatments for these diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Koenig, James I
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University of Wisconsin Madison
Schools of Medicine
United States
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Ma, Shang; Santhosh, Devi; Kumar T, Peeyush et al. (2017) A Brain-Region-Specific Neural Pathway Regulating Germinal Matrix Angiogenesis. Dev Cell 41:366-381.e4
Santhosh, Devi; Huang, Zhen (2016) A Tie2-driven BAC-TRAP transgenic line for in vivo endothelial gene profiling. Genesis 54:136-45
Santhosh, Devi; Huang, Zhen (2015) Regulation of the nascent brain vascular network by neural progenitors. Mech Dev 138 Pt 1:37-42
Ma, Shang; Huang, Zhen (2015) Neural Regulation of CNS Angiogenesis During Development. Front Biol (Beijing) 10:61-73
Ma, Shang; Kwon, Hyo Jun; Johng, Heidi et al. (2013) Radial glial neural progenitors regulate nascent brain vascular network stabilization via inhibition of Wnt signaling. PLoS Biol 11:e1001469
Ma, Shang; Kwon, Hyo Jun; Huang, Zhen (2012) A functional requirement for astroglia in promoting blood vessel development in the early postnatal brain. PLoS One 7:e48001