Vascular aging, the vascular cytoskeleton and aortic stiffness

Kajuluri, Lova Prasadareddy; Singh, Kuldeep; Morgan, Kathleen G.

doi:10.37349/emed.2021.00041

Cited by 9 publications

(14 citation statements)

References 98 publications

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“…The stiffening of the conduit arteries is one of the characteristics of arterial aging 41 . The stiffness of the artery is largely dependent on the elevated collagen to elastin ratio and calcium deposition within the vessel wall 42 , 43 .…”

Section: Discussionmentioning

confidence: 99%

MFG-E8 promotes osteogenic transdifferentiation of smooth muscle cells and vascular calcification by regulating TGF-β1 signaling

et al. 2022

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Vascular calcification occurs in arterial aging, atherosclerosis, diabetes mellitus, and chronic kidney disease. Transforming growth factor-β1 (TGF-β1) is a key modulator driving the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs), leading to vascular calcification. We hypothesize that milk fat globule–epidermal growth factor 8 (MFG-E8), a glycoprotein expressed in VSMCs, promotes the osteogenic transdifferentiation of VSMCs through the activation of TGF-β1-mediated signaling. We observe that the genetic deletion of MFG-E8 prevents calcium chloride-induced vascular calcification in common carotid arteries (CCAs). The exogenous application of MFG-E8 to aged CCAs promotes arterial wall calcification. MFG-E8-deficient cultured VSMCs exhibit decreased biomineralization and phenotypic transformation to osteoblast-like cells in response to osteogenic medium. MFG-E8 promotes β1 integrin–dependent MMP2 expression, causing TGF-β1 activation and subsequent VSMC osteogenic transdifferentiation and biomineralization. Thus, the established molecular link between MFG-E8 and vascular calcification suggests that MFG-E8 can be therapeutically targeted to mitigate vascular calcification.

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Section: Discussionmentioning

confidence: 99%

MFG-E8 promotes osteogenic transdifferentiation of smooth muscle cells and vascular calcification by regulating TGF-β1 signaling

et al. 2022

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“…Disruption in α-SMA contractile filaments lead to dysfunction in cytoskeletal tension development in response to stimuli [46], and thereby, is responsible for a decline in VSMC mechanosensation. In addition, γ-SMA in VSMCs resides mainly near the cell cortex and take part in force transmission along the actomyosin-focal adhesion-integrin axis [47]. An increased in γ-SMA has been implied to be a contributor of increased cortical stiffness in previous studies [14,47,48].…”

Section: Csk Architectures Indicates That Old Vsmcs Have Disrupted Ac...mentioning

confidence: 95%

“…In addition, γ-SMA in VSMCs resides mainly near the cell cortex and take part in force transmission along the actomyosin-focal adhesion-integrin axis [47]. An increased in γ-SMA has been implied to be a contributor of increased cortical stiffness in previous studies [14,47,48]. In aged cells, distribution of γ-SMA stress fiber along the cytoplasm in the absence of α-SMA promoted a stiffening CSK, as indicated by the lower ratio of α-SMA (contractile element) to γ-SMA (stiffening element) in old cells relative to the young cells (Fig.…”

Section: Csk Architectures Indicates That Old Vsmcs Have Disrupted Ac...mentioning

confidence: 99%

Aging-associated Decline in Vascular Smooth Muscle Cell Mechanosensation is Mediated by Piezo1 Channel

Luu

Bajpai

et al. 2023

Preprint

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Aging of the vasculature is associated with detrimental changes in vascular smooth muscle cell (VSMC) mechanosensitivity to extrinsic forces in their surrounding microenvironment. However, how chronological aging alters VSMCs ability to sense and adapt to mechanical perturbations remains unexplored. Here, we show defective VSMC mechanosensation in aging measured with ultrasound tweezers-based micromechanical system, force instantaneous frequency spectrum and transcriptome analyses. The mechanobiological study reveals that aged VSMCs adapt a relatively inert solid-like state with altered actin cytoskeletal integrity, resulting in an impairment in their mechanosensitivity and dynamic mechanoresponse to mechanical perturbations. The aging-associated decline in mechanosensation behaviors is mediated by hyperactivity of Piezo1-dependent calcium signaling. Inhibition of Piezo1 alleviates vascular aging and partially restores the loss in dynamic contractile properties in aged cells. Altogether, our study reveals the novel signaling pathway underlying aging-associated aberrant mechanosensation in VSMC and identifies Piezo1 as a potential therapeutic mechanobiological target to alleviate vascular aging.

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“…Arterial stiffening involves changes in extracellular components of the arterial wall due to proteolytic degradation of elastin fibers shifting the load towards stiffer collagen fibres ( Duca et al, 2016 ). VSMCs also undergo age-dependent changes such as alterations in the activity of the contractile filaments as well as in the molecular signaling pathways regulating actin polymerization, both directly contributing to the vascular stiffening ( Kajuluri et al, 2021 ). Furthermore, adhesion to the extracellular matrix is increased ( Zhu et al, 2012 ).…”

Section: Coronary Microvascular Function and Structure In Diseasementioning

confidence: 99%

Mechanobiology of Microvascular Function and Structure in Health and Disease: Focus on the Coronary Circulation

et al. 2021

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The coronary microvasculature plays a key role in regulating the tight coupling between myocardial perfusion and myocardial oxygen demand across a wide range of cardiac activity. Short-term regulation of coronary blood flow in response to metabolic stimuli is achieved via adjustment of vascular diameter in different segments of the microvasculature in conjunction with mechanical forces eliciting myogenic and flow-mediated vasodilation. In contrast, chronic adjustments in flow regulation also involve microvascular structural modifications, termed remodeling. Vascular remodeling encompasses changes in microvascular diameter and/or density being largely modulated by mechanical forces acting on the endothelium and vascular smooth muscle cells. Whereas in recent years, substantial knowledge has been gathered regarding the molecular mechanisms controlling microvascular tone and how these are altered in various diseases, the structural adaptations in response to pathologic situations are less well understood. In this article, we review the factors involved in coronary microvascular functional and structural alterations in obstructive and non-obstructive coronary artery disease and the molecular mechanisms involved therein with a focus on mechanobiology. Cardiovascular risk factors including metabolic dysregulation, hypercholesterolemia, hypertension and aging have been shown to induce microvascular (endothelial) dysfunction and vascular remodeling. Additionally, alterations in biomechanical forces produced by a coronary artery stenosis are associated with microvascular functional and structural alterations. Future studies should be directed at further unraveling the mechanisms underlying the coronary microvascular functional and structural alterations in disease; a deeper understanding of these mechanisms is critical for the identification of potential new targets for the treatment of ischemic heart disease.

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Vascular aging, the vascular cytoskeleton and aortic stiffness

Cited by 9 publications

References 98 publications

MFG-E8 promotes osteogenic transdifferentiation of smooth muscle cells and vascular calcification by regulating TGF-β1 signaling

MFG-E8 promotes osteogenic transdifferentiation of smooth muscle cells and vascular calcification by regulating TGF-β1 signaling

Aging-associated Decline in Vascular Smooth Muscle Cell Mechanosensation is Mediated by Piezo1 Channel

Mechanobiology of Microvascular Function and Structure in Health and Disease: Focus on the Coronary Circulation

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