Dataset Information

LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Regulates Smooth Muscle Contractility by Modulating Ca2+ Signaling and Expression of Cytoskeleton-Related Proteins.

ABSTRACT: Objective- Mutations affecting contractile-related proteins in the ECM (extracellular matrix), microfibrils, or vascular smooth muscle cells can predispose the aorta to aneurysms. We reported previously that the LRP1 (low-density lipoprotein receptor-related protein 1) maintains vessel wall integrity, and smLRP1-/- mice exhibited aortic dilatation. The current study focused on defining the mechanisms by which LRP1 regulates vessel wall function and integrity. Approach and Results- Isometric contraction assays demonstrated that vasoreactivity of LRP1-deficient aortic rings was significantly attenuated when stimulated with vasoconstrictors, including phenylephrine, thromboxane receptor agonist U-46619, increased potassium, and L-type Ca2+ channel ligand FPL-64176. Quantitative proteomics revealed proteins involved in actin polymerization and contraction were significantly downregulated in aortas of smLRP1-/- mice. However, studies with calyculin A indicated that although aortic muscle from smLRP1-/- mice can contract in response to calyculin A, a role for LRP1 in regulating the contractile machinery is not revealed. Furthermore, intracellular calcium imaging experiments identified defects in calcium release in response to a RyR (ryanodine receptor) agonist in smLRP1-/- aortic rings and cultured vascular smooth muscle cells. Conclusions- These results identify a critical role for LRP1 in modulating vascular smooth muscle cell contraction by regulating calcium signaling events that potentially protect against aneurysm development.

SUBMITTER: Au DT

PROVIDER: S-EPMC6214382 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Regulates Smooth Muscle Contractility by Modulating Ca<sup>2+</sup> Signaling and Expression of Cytoskeleton-Related Proteins.

Au Dianaly T DT Ying Zhekang Z Hernández-Ochoa Erick O EO Fondrie William E WE Hampton Brian B Migliorini Mary M Galisteo Rebeca R Schneider Martin F MF Daugherty Alan A Rateri Debra L DL Strickland Dudley K DK Muratoglu Selen C SC

Arteriosclerosis, thrombosis, and vascular biology 20181101 11

Objective- Mutations affecting contractile-related proteins in the ECM (extracellular matrix), microfibrils, or vascular smooth muscle cells can predispose the aorta to aneurysms. We reported previously that the LRP1 (low-density lipoprotein receptor-related protein 1) maintains vessel wall integrity, and smLRP1<sup>-/-</sup> mice exhibited aortic dilatation. The current study focused on defining the mechanisms by which LRP1 regulates vessel wall function and integrity. Approach and Results- Iso ...[more]

PMID: 30354243

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Project description:Astrocytes are the most abundant cell type within the central nervous system (CNS) with various functions. Furthermore, astrocytes show a regional and developmental heterogeneity traceable with specific markers. In this study, the influence of the low-density lipoprotein receptor-related protein 1 (LRP1) on astrocytic maturation within the hippocampus was analyzed during development. Previous studies mostly focused on the involvement of LRP1 in the neuronal compartment, where the deletion caused hyperactivity and motor dysfunctions in knockout animals. However, the influence of LRP1 on glia cells is less intensively investigated. Therefore, we used a newly generated mouse model, where LRP1 is specifically deleted from GLAST-positive astrocytes co-localized with the expression of the reporter tdTomato to visualize recombination and knockout events in vivo. The influence of LRP1 on the maturation of hippocampal astrocytes was assessed with immunohistochemical stainings against stage-specific markers as well as on mRNA level with RT-PCR analysis. The examination revealed that the knockout induction caused a significantly decreased number of mature astrocytes at an early developmental timepoint compared to control animals. Additionally, the delayed maturation of astrocytes also caused a reduced activity of neurons within the hippocampus. As previous studies showed that the glial specification and maturation of astrocytes is dependent on the signaling cascades Ras/Raf/MEK/Erk and PI3K/Akt, the phosphorylation of the signaling molecules Erk1/2 and Akt was analyzed. The hippocampal tissue of LRP1-deficient animals at P21 showed a significantly decreased amount of activated Erk in comparison to control tissue leading to the conclusion that the activation of this signaling cascade is dependent on LRP1 in astrocytes, which in turn is necessary for proper maturation of astrocytes. Our results showed that the deletion of LRP1 at an early developmental timepoint caused a delayed maturation of astrocytes in the hippocampus based on an altered activation of the Ras/Raf/MEK/Erk signaling pathway. However, with ongoing development these effects were compensated and the number of mature astrocytes was comparable as well as the activity of neurons. Therefore, LRP1 acts as an early regulator of the differentiation and maturation of astrocytes within the hippocampus.

Dataset Information

LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Regulates Smooth Muscle Contractility by Modulating Ca2+ Signaling and Expression of Cytoskeleton-Related Proteins.

Publications

LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Regulates Smooth Muscle Contractility by Modulating Ca<sup>2+</sup> Signaling and Expression of Cytoskeleton-Related Proteins.

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