ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

Albacete-Albacete, Lucas; Navarro-Lérida, Inmaculada; López, Juan Antonio; Martín‐Padura, Inés; Astudillo, Alma M.; Van‐Der‐Heyden, Michael; Balsinde, Jesús; Orend, Gertraud; Vázquez, Jesús; Pozo, Miguel Á. del

doi:10.1101/405506

Cited by 4 publications

(2 citation statements)

References 76 publications

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“…36 Moreover, Cav1/ caveolae have been also shown to regulate FN internalization and degradation and more recently with the secretion of FN via exosome-regulated process. 37 Additional studies will be required to define the specific mechanism by which EC Cav1/caveolae controls ECM changes in athero-prone areas during the progression of atherosclerosis but it is likely that a combination of the processes described above might contribute to the alteration in ECM composition observed in Cav1 deficient mice. Moreover, we also found that absence of Cav1 in ECs expose to disturbed flow impairs the activation of NFkB signaling pathway and attenuates the OSS-primed inflammatory response to pro-atherogenic cytokines including TNFα and IL1β.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation

et al. 2019

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Background-Atherosclerosis is driven by synergistic interactions between pathological biomechanical, inflammatory and lipid metabolic factors. Our previous studies demonstrated that absence of caveolin-1 (Cav1)/caveolae in hyperlipidemic mice strongly inhibits atherosclerosis, which was attributed to activation of endothelial nitric oxide synthase (eNOS) and increased production of nitric oxide (NO), reduced inflammation and low-density lipoprotein (LDL) trafficking. However, the contribution of eNOS activation and NO production in the athero-protection of Cav1 and the exact mechanisms by which Cav1/caveolae controls the pathogenesis of diet-induced atherosclerosis are still not clear. Methods-Triple knockout mouse lacking expression of eNOS, Cav1 and Ldlr were generated to explore the role of NO production in Cav1-dependent atheo-protective function. The effects of Cav1 on lipid trafficking, extracellular matrix (ECM) remodeling and vascular inflammation were studied both in vitro and in vivo using a mouse model of diet-induced atherosclerosis. The expression of Cav1 and distribution of caveolae regulated by flow were analyzed by immunofluorescence staining and transmission electron microscopy. Results-We found that absence of Cav1 significantly suppressed atherogenesis in Ldlr −/− eNOS −/− mice, demonstrating that athero-suppression is independent of increased NO production. Instead, we find that absence of Cav1/caveolae inhibited LDL transport across the endothelium, pro-atherogenic fibronectin deposition, and disturbed flow-mediated endothelial cell (EC) inflammation. Consistent with the idea that Cav1/caveolae may play a role in early flowdependent inflammatory priming, distinct patterns of Cav1 expression and caveolae distribution were observed in athero-prone and athero-resistant areas of the aortic arch even in wild-type mice. Conclusions-The above findings support a role for Cav1/caveolae as a central regulator of atherosclerosis that links biomechanical, metabolic and inflammatory pathways independent of endothelial eNOS activation and NO production.

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Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation

et al. 2019

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“…Its structure and composition, including ECM-associated proteins such as growth factors, control most if not all aspects of tumor pathology (58)(59)(60). It is now evident that EVs have an essential role in the ECM biology: EVs can be functional components of the ECM (32,34) and CM-EVs control ECM deposition (61) and remodeling (62). Our work provides a first evidence that CAFs deposit EVs in the matrix and that MBVs play a key role as vehicles for intercellular protein transfer.…”

Section: Discussionmentioning

confidence: 69%

Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function

Santi

Kay

Neilson

et al. 2023

Preprint

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Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we unveil a mechanism of cell-cell communication between CAFs with myofibroblast phenotype and endothelial cells (ECs) based on intercellular protein transfer through extracellular vesicles (EVs). CAFs transfer proteins to ECs, including plasma membrane receptors, which we have identified by using mass spectrometry-based proteomics. Using THY1 as an example of transferred plasma membrane-bound protein, we show that CAF-derived proteins can influence how ECs interact with other cell types. Here, we show that CAFs produce high amounts of matrix-bound EVs that have a key role in protein transfer. Hence, our work paves the way for further studies to understand how CAF-derived matrix-bound EVs influence tumor pathology by regulating functions of neighboring cancer, stromal and immune cells.

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Tumor-stroma biomechanical crosstalk: a perspective on the role of caveolin-1 in tumor progression

Lolo

Jiménez-Jiménez

Sánchez-Álvarez

et al. 2020

Cancer Metastasis Rev

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ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

Cited by 4 publications

References 76 publications

Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation

Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation

Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function

Tumor-stroma biomechanical crosstalk: a perspective on the role of caveolin-1 in tumor progression

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