Assembly of vascular smooth muscle cells in 3D aggregates provokes cellular quiescence

Jäger, Marius Andreas; Torre, Carolina De La; Arnold, Caroline; Kohlhaas, Johanna; Kappert, Lena; Hecker, Markus; Feldner, Anja; Korff, Thomas

doi:10.1016/j.yexcr.2019.111782

Cited by 13 publications

(14 citation statements)

References 34 publications

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“…For further mechanistic analyses addressing the consequences of Rgs5 deficiency, we required an experimental setup that maintains Rgs5 expression in cultured mouse aortic VSMCs. We applied a 3D spheroid culture technique that allows the formation of multiple SMC layers and promotes a differentiated, contractile and quiescent VSMC phenotype [ 26 ]. As compared to proliferating murine VSMCs cultured under 2D conditions, Rgs5 expression was upregulated in 3D spheroids ( Figure 3 a) while its knockout ( Figure 3 b) was associated with increased ERK1/2 phosphorylation ( Figure 3 c).…”

Section: Resultsmentioning

confidence: 99%

“…On the cellular level, Rgs5 expression was increased in VSMCs or arteries exposed to nitric oxide or biomechanical stretch [ 17 , 21 ] and repressed in VSMCs under mitogenic culture conditions [ 20 ] or after treatment with platelet-derived growth factor [ 33 ]. Here, we show that the low expression level of RGS5 in proliferating VSMCs is robustly increased under 3D culture conditions supporting the resting VSMC phenotype [ 26 ]. In this context, RGS5 appears to act as a determinant of cellular quiescence as it attenuates Gα q/11 and Gα i/o -protein activity, and significantly alters the activity of downstream signaling cascades.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, RGS5 promotes the baseline activity of RhoA confirming earlier observations and its link with Gα i/o and Gα q/11 —mediated signaling events [ 21 ]. Functionally, RhoA activity stimulates the expression of prototypic SMC markers, such as αSMA and SM22 [ 27 ]—a hallmark of a contractile and quiescent VSMC phenotype that predominates under the chosen 3D culture conditions [ 26 ]. Moreover, RhoA may also contribute to transforming growth factor-β-dependent Smad signaling, which supports VSMC differentiation [ 34 , 35 ] and is critical for preserving the growth arrest in 3D VSMC spheroids [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

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RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells

Demirel

Arnold

Garg

et al. 2021

Cells

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The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gαq/11 and Gαi/o activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC responses during various vascular remodeling processes, its regulatory features in resting VSMCs and its impact on their phenotype are still under debate and were subject of this study. While Rgs5 shows a variable expression in mouse arteries, neither global nor SMC-specific genetic ablation of Rgs5 affected the baseline blood pressure yet elevated the phosphorylation level of the MAP kinase ERK1/2. Comparable results were obtained with 3D cultured resting VSMCs. In contrast, overexpression of RGS5 in 2D-cultured proliferating VSMCs promoted their resting state as evidenced by microarray-based expression profiling and attenuated the activity of Akt- and MAP kinase-related signaling cascades. Moreover, RGS5 overexpression attenuated ERK1/2 phosphorylation, VSMC proliferation, and migration, which was mimicked by selectively inhibiting Gαi/o but not Gαq/11 activity. Collectively, the heterogeneous expression of Rgs5 suggests arterial blood vessel type-specific functions in mouse VSMCs. This comprises inhibition of acute agonist-induced Gαq/11/calcium release as well as the support of a resting VSMC phenotype with low ERK1/2 activity by suppressing the activity of Gαi/o.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells

Demirel

Arnold

Garg

et al. 2021

Cells

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“…Collagen has pleiotropic effects on VSMC phenotype depending on the type of collagen deposited. Furthermore, while collagen I and fibronectin induce synthetic VSMCs phenotype [ 99 , 100 ], secretion of collagen type-IV by cells promote a contractile VSMCs phenotype signal transduction [ 99 , 100 , 101 , 102 , 103 , 104 , 105 ].…”

Section: Ec–vsmc Communicationmentioning

confidence: 99%

“…Studies in EC spheroids have described that oxidized phospholipid [ 142 ] or supernatants of activated natural killer (NK) cells [ 143 ] promoted growth of capillaries in the context of atherosclerosis lesion progression. Recently, the assessed of a spheroid model of human endothelial and vascular cells has been used to study the impact of ECs on the gene expression pattern of VSMCs [ 105 ]. In this model, different source of human EC and VSMCs were cultured in suspended cell spheres, which spontaneously organized into a central composite VSMCs core enclosed by a human EC monolayer.…”

Section: In Vitro Models To Study Ec–vsmcs Communication During Vascular Remodelingmentioning

confidence: 99%

Cellular Crosstalk between Endothelial and Smooth Muscle Cells in Vascular Wall Remodeling

Méndez‐Barbero

Gutiérrez-Muñoz

Blanco-Colio

2021

IJMS

104

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Pathological vascular wall remodeling refers to the structural and functional changes of the vessel wall that occur in response to injury that eventually leads to cardiovascular disease (CVD). Vessel wall are composed of two major primary cells types, endothelial cells (EC) and vascular smooth muscle cells (VSMCs). The physiological communications between these two cell types (EC–VSMCs) are crucial in the development of the vasculature and in the homeostasis of mature vessels. Moreover, aberrant EC–VSMCs communication has been associated to the promotor of various disease states including vascular wall remodeling. Paracrine regulations by bioactive molecules, communication via direct contact (junctions) or information transfer via extracellular vesicles or extracellular matrix are main crosstalk mechanisms. Identification of the nature of this EC–VSMCs crosstalk may offer strategies to develop new insights for prevention and treatment of disease that curse with vascular remodeling. Here, we will review the molecular mechanisms underlying the interplay between EC and VSMCs. Additionally, we highlight the potential applicable methodologies of the co-culture systems to identify cellular and molecular mechanisms involved in pathological vascular wall remodeling, opening questions about the future research directions.

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In vitro 3D co-culture model of human endothelial and smooth muscle cells to study pathological vascular remodeling

San Sebastián-Jaraba,

Fernández-Gómez,

Blázquez-Serra

et al. 2024

Clínica e Investigación en Arteriosclerosis (English Edition)

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Assembly of vascular smooth muscle cells in 3D aggregates provokes cellular quiescence

Cited by 13 publications

References 34 publications

RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells

RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells

Cellular Crosstalk between Endothelial and Smooth Muscle Cells in Vascular Wall Remodeling

In vitro 3D co-culture model of human endothelial and smooth muscle cells to study pathological vascular remodeling

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