Laminin Beta 2 Is Localized at the Sites of Blood-Brain Barrier and Its Disruption Is Associated With Increased Vascular Permeability, Histochemical, and Transcriptomic Study.
Publication Year:
2024
PubMed ID:
39340425
Funding Grants:
Public Summary:
Laminins are proteins important for blood vessel health, especially in the brain’s protective blood-brain barrier (BBB). Normally, the brain’s tiny blood vessels are covered by laminin beta 2 (LAMB2), which helps keep the barrier strong. Another laminin, beta 1 (LAMB1), is usually absent but appears when new blood vessels grow. In aggressive brain tumors (high-grade gliomas), LAMB1 increases a lot while LAMB2 decreases, which weakens the blood vessels and the BBB. Treatments that block blood vessel growth stop LAMB1 from appearing and bring back LAMB2, helping to restore normal blood vessel function. Studies show that in a healthy brain, LAMB2 is made by cells supporting the blood vessels, but in tumors, immature blood vessel cells produce both LAMB1 and LAMB2, contributing to abnormal vessel growth.
Scientific Abstract:
Heterotrimeric extracellular matrix proteins laminins are mostly deposited at basal membranes and are important in repair and neoplasia. Here, we localize laminin beta 2 (LAMB2) at the sites of blood-brain barrier (BBB). Microvasculature (MV) of normal brain is endowed with complete LAMB2 coverage. In contrast, its cognate protein laminin beta 1 (LAMB1) is absent in MV of normal brain but emerges at the sprouting tip of a growing vessels. Similarly, vascular proliferation in high-grade gliomas (HGG) is accompanied by marked overexpression of LAMB1, whereas LAMB2 shows deficient deposition. We find that many brain pathologies with presence of post-gadolinium enhancement (PGE) on magnetic resonance imaging (MRI) show disruption of LAMB2 vascular ensheathment. Inhibition of vascular endothelial growth factor signaling in HGG blocks angiogenesis, suppresses PGE in HGG, prevents expression of LAMB1, and restores LAMB2 vascular coverage. Analysis of single-cell RNA sequencing (scRNA-seq) databases shows that in quiescent brain LAMB2 is predominantly expressed by BBB-associated pericytes (PCs) and endothelial cells (ECs), whereas neither cell types produce LAMB1. In contrast, in HGG, both LAMB1 and 2 are overexpressed by endothelial precursor cells, a phenotypically unique immature group, specific to proliferating hyperplastic MV.