MAILMAN RESEARCH CENTER
Angiogenesis & Brain Development Laboratory
The anatomy of the brain's vascular networks is as complex and fascinating as that of its neuronal networks. Yet, despite the remarkable progress in our understanding of the development of neuronal networks, the mechanisms regulating central nervous system (CNS) angiogenesis are not well understood. Our work has challenged notions of cerebral vascularization which imply that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations or treat endothelial cells of the CNS as a homogenous population. Blood vessel development in the embryonic forebrain (telencephalon) is not a passive process and does not shadow neuronal development. Based on origins, anatomical location, independent growth patterns and developmental regulation, telencephalic blood vessels fall into two categories: pial and periventricular. While the neural tube directs the formation of the pial vascular network that encompasses it by embryonic day 9 (E9), the periventricular vascular network are branches of a basal vessel located in the basal ganglia primordium and develops in an orderly, ventral-to-dorsal gradient orchestrated by compartment-specific gene expression by E11. These two embryonic vascular networks precede neuronal networks, radial units of the dorsal telencephalon or striosome-matrix compartments of the ventral telencephalon. Interestingly, the direction of propagation of the periventricular endothelial cell gradient corresponds to the transverse neurogenetic gradient and tangential migration of GABA neurons in the embryonic telencephalon. With respect to timing, the angiogenesis gradient is in advance of the neuronal gradients by about a day. Recent studies in my laboratory show that periventricular endothelial cells provide critical cues to instruct neurogenesis and neuronal migration. There is remarkable endothelial cell diversity and function in the embryonic telencephalon leading to many important questions regarding specifically expressed genes in individual populations of endothelial cells based on their position in the CNS. Furthermore, the angiogenesis, neurogenesis and GABA neuron developmental gradients are related to one another at mechanistic levels. Intrinsic neuronal defects thus far believed to cause many neurological and psychiatric diseases like schizophrenia, epilepsy and autism may in fact be a consequence of common molecular signals defective specifically in these endothelial cells. The goal of our research is thus to understand in detail the autonomous roles of CNS angiogenesis and its significance for brain development and disease.
Using a combination of developmental biology, mouse genetics, cell biology, biochemistry and imaging techniques, our research program currently explores 4 topics:
- Explore molecular mechanisms underlying cell-autonomous programs that regulate endothelial cell development in the forebrain.
- Characterize the mechanistic basis of endothelial cell-GABA neuron interactions in the developing CNS.
- To selectively impair periventricular endothelial cell development using in vivo/genetic approaches and study the consequences on neuronal development.
- Tap into the potential of periventricular endothelial cells as a therapeutic source for recovery of neurological function in many diverse scenarios.
- Anju Vasudevan PhD - Assistant Professor of Psychiatry (email: email@example.com)
- Suyan Li PhD â€“ Postdoctoral Fellow (email: firstname.lastname@example.org)
- Peeyush Kumar TP PhD â€“ Postdoctoral Fellow (email: Peeyush.Pandit@mclean.harvard.edu)
- Chungkil Won, PhD â€“ Postdoctoral Associate (email: email@example.com)
- National Institute of Neurological Disorders and Stroke (NINDS)
- National Alliance for Research on Schizophrenia and Depression (NARSAD)
- Li S, Haigh K, Haigh, JJ and Vasudevan A. Endothelial VEGF sculpts cortical cytoarchitecture. The Journal of Neuroscience; in press.
- Kumar PT and Vasudevan A. Isolation and culture of endothelial cells from the embryonic forebrain. JOVE; in press.
- Won CK, Lin Z, Kumar PT, Li S, Ding L, ElKhal A, Szabo G and Vasudevan A.Â Autonomous vascular networks synchronize GABA neuron migration in the embryonic forebrain. Nature Communications; 2013;4:2149. doi: 10.1038/ncomms3149.
- Vasudevan A, Won CK, Li S, Erdelyi, F, Szabo G and Kim KS. Dopaminergic neurons modulate GABA neuron migration in the embryonic midbrain. Development; 2012; 139(17): 3136-41.
- Vasudevan A, Ho MSP, Weiergraber M, Nischt R, Schneider T, Lie A, Smyth N and Köhling R. Basement membrane protein nidogen-1 shapes hippocampal synaptic plasticity and excitability. Hippocampus; 2010; 20(5):608-20.
- Vasudevan A, Long JE, Crandall JE, Rubenstein JLR and Bhide PG. Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain. Nature Neuroscience; 2008; 11(4): 429-39.