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Vascular Basement Membrane Laminins Modulate Functional Zonation of Cerebral Microvessels [scRNA-seq]

ABSTRACT: We investigated whether vascular basement membrane (BM) laminins influence vascular zonation by performing single-cell RNA sequencing (scRNAseq) on cerebral blood vessels from Lama4-/- mice - lacking the major vascular laminin 4 in endothelial and smooth muscle BMs - and wild-type littermates. Our dataset expands existing cerebral vascular transcriptomic profiles and reveals that Lama4-/- endothelial cells exhibit increased arterial marker expression and reduced postcapillary venule identity. In vitro and in vivo studies indicate that compensatory upregulation of laminin 5 in Lama4-/- vessels enhances expression of junctional proteins (Ocln, Cldn5) and promotes vessel contractility via increased expression of contractile genes in pericytes, which reside within the endothelial BM. Additionally, loss of Lama4 upregulates expression of large artery markers (Gja4, Dll4, Edn1,Tgfb2) and resulted in elevated autotaxin (Enpp2) levels, a key enzyme in lysophosphatidic acid production implicated in stroke. Accordingly, Lama4-/- mice exhibit worsened stroke outcomes, driven not by immune infiltration or junctional defects, but by increased vascular permeability likely mediated by autotaxin and/or activation of resident myeloid cells. Our data suggest that laminin 4/5 ratios in vascular BMs regulate functional zonation between arterioles, capillaries and postcapillary venules by modulating metabolic pathways in endothelial and mural cells, and indirectly influencing resident myeloid cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE308748 | GEO | 2026/02/25

REPOSITORIES: GEO

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Vascular Basement Membrane Laminins Modulate Functional Zonation of Cerebral Microvessels [RNA-seq]

Project description:We investigated whether vascular basement membrane (BM) laminins influence vascular zonation by performing single-cell RNA sequencing (scRNAseq) on cerebral blood vessels from Lama4-/- mice - lacking the major vascular laminin 4 in endothelial and smooth muscle BMs - and wild-type littermates. Our dataset expands existing cerebral vascular transcriptomic profiles and reveals that Lama4-/- endothelial cells exhibit increased arterial marker expression and reduced postcapillary venule identity. In vitro and in vivo studies indicate that compensatory upregulation of laminin 5 in Lama4-/- vessels enhances expression of junctional proteins (Ocln, Cldn5) and promotes vessel contractility via increased expression of contractile genes in pericytes, which reside within the endothelial BM. Additionally, loss of Lama4 upregulates expression of large artery markers (Gja4, Dll4, Edn1,Tgfb2) and resulted in elevated autotaxin (Enpp2) levels, a key enzyme in lysophosphatidic acid production implicated in stroke. Accordingly, Lama4-/- mice exhibit worsened stroke outcomes, driven not by immune infiltration or junctional defects, but by increased vascular permeability likely mediated by autotaxin and/or activation of resident myeloid cells. Our data suggest that laminin 4/5 ratios in vascular BMs regulate functional zonation between arterioles, capillaries and postcapillary venules by modulating metabolic pathways in endothelial and mural cells, and indirectly influencing resident myeloid cells.

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Basement Membranes from Human Retinal Blood Vessels, Inner Limiting Membranes, and Lens Capsules

Project description:Three types of BMs from adult human eyes, the inner limiting membrane, the retinal vascular BMs and the lens capsule, were isolated for analysis by 1D-SDS-PAGE and LC-MS/MS.

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Blood vessel-resident macrophages safeguard blood and vessel integrity in zebrafish

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mRAN expression profiles in mesenchymal progenitor cells freshly-sorted from Wild Type and Lama4-deficient mice

Project description:Bone marrow (BM) niche contributes to hematopoietic regeneration under stress like irradiation and leukemia. However, the mechanisms remain poorly defined. We here report that Lama4 deletion in mice results in reduction of mesenchymal progenitors (MPCs) and endothelial cells in BM. Following irradiation, Lama4-/- mice displayed impaired hematopoiesis recovery accompanied with dysregulation of BM niche factors like angiopoietin-1 and Tgfb1 in the MPCs. Post-transplantation of MLL-AF9 acute myeloid leukemia (AML) cells, we observed accelerated AML onset in Lama4-/- mice. Moreover, these Lama4-/- AML mice displayed faster relapse after therapeutic BM transplantation. Mechanistically, Lama4-/- niche promoted AML cell proliferation and chemoresistance to chemotherapy cytarabine by conferring AML greater antioxidant activity. Together, our study demonstrates that Lama4 is required to maintain hematopoietic niche integrity and to suppress AML progression and chemoresistance by restricting metabolic defense support to AML. Therefore, activating Lama4 signaling pathways may offer potential new therapeutic options for AML.

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Basement Membranes from Human Retinal Blood Vessels, Inner Limiting Membranes, and Lens Capsules

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