The study of neuro-vascular interactions in the central nervous system

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

1) CNS blood and lymphatic vessel development. Our extensive immunohistochemical studies have revealed Prox1-/LYVE1+ individual cells distributed in the pial layer of brain and spinal cord during early developmental stages. Interestingly, LYVE-1+ cells with macrophage-like morphology, known as brain mural lymphatic endothelial cells, have been reported on the surface of the zebrafish brain. Our lineage tracing studies indicate that the LYVE1+ cells in the pial layer are meningeal perivascular macrophages, but not lymphatic endothelial cells. This suggests that, unlike in the zebrafish brain, no lymphatic endothelial cells or progenitors develop near the CNS parenchyma in mammal. Moreover, our further studies reveal that LYVE-1+ macrophages regulates the mitosis of radial glia cell (RGC)-the primary source of cortical neurons during early brain development- via their endfeet on the meninx, through an IGF1-Akt signaling-dependent manner (Liu, Sato, et al. Manuscript in preparation). These data underscore the critical role of the pial macrophage-RGC interaction in cortical development. 2) A potential molecular link between BBB integrity and lymphatic avascularity BBB dysfunction is a hallmark of neurovascular diseases, such as glioblastoma and brain metastases. Prox1, a key transcription factor for lymphatic differentiation, is normally absent in CNS endothelial cells (ECs); however, our analysis of publicly available single-cell RNA sequencing datasets from patients with glioblastoma and brain metastases revealed that Prox1, along with the vascular permeability marker PLVAP, is aberrantly expressed in ECs across all these conditions. These findings suggest that Prox1 may contribute to vascular abnormalities and BBB disruption. To address this further, we generated a mouse model with inducible Prox1 overexpression in ECs. This led to vascular malformations, increased permeability, and BBB disruption when induced postnatally or adult stages, demonstrating that Prox1-mediated vascular defects occur independently of the timing of development. Mechanistically, PROX1 directly represses the expression of Claudin-5 and β-catenin, which are key regulators of BBB integrity, resulting in impaired tight junctions and increased transcytosis (González-Hernández et al. Revision Submitted; bioRxiv PMID: 39803470). We are currently focusing on managing endothelial Prox1 expression in mouse models of glioblastoma to test if this intervention can restore BBB integrity and improve treatment outcome for glioblastoma.