Differential cell-matrix responses in hypoxia-stimulated aortic versus mitral valves

Sapp, Matthew C.; Krishnamurthy, Varun K.; Puperi, Daniel S.; Bhatnagar, Saheba; Fatora, Gabrielle; Mutyala, Neelesh; Grande‐Allen, K. Jane

doi:10.1098/rsif.2016.0449

Cited by 21 publications

(21 citation statements)

References 42 publications

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“…Hypoxia has been implicated as a contributing factor in valve disease progression, as O 2 diffusion might not be as efficient as the valve becomes thickened in MMVD. In addition, loss of ECM stratification is observed in adult porcine aortic and mitral valves cultured under hypoxic conditions (27). In the present study, we show that exposure of adult mice to hypoxia leads to increased indicators of HA remodeling, supporting a role for O 2 in the maintenance of GAG expression in normal heart valves.…”

Section: Discussionsupporting

confidence: 69%

Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves

Amofa

Hulin

Nakada

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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During postnatal heart valve development, glycosaminoglycan (GAG)-rich valve primordia transform into stratified valve leaflets composed of GAGs, fibrillar collagen, and elastin layers accompanied by decreased cell proliferation as well as thinning and elongation. The neonatal period is characterized by the transition from a uterine environment to atmospheric O, but the role of changing O levels in valve extracellular matrix (ECM) composition or morphogenesis is not well characterized. Here, we show that tissue hypoxia decreases in mouse aortic valves in the days after birth, concomitant with ECM remodeling and cell cycle arrest of valve interstitial cells. The effects of hypoxia on late embryonic valve ECM composition, Sox9 expression, and cell proliferation were examined in chicken embryo aortic valve organ cultures. Maintenance of late embryonic chicken aortic valve organ cultures in a hypoxic environment promotes GAG expression, Sox9 nuclear localization, and indicators of hyaluronan remodeling but does not affect fibrillar collagen content or cell proliferation. Chronic hypoxia also promotes GAG accumulation in murine adult heart valves in vivo. Together, these results support a role for hypoxia in maintaining a primitive GAG-rich matrix in developing heart valves before birth and also in the induction of hyaluronan remodeling in adults. Tissue hypoxia decreases in mouse aortic valves after birth, and exposure to hypoxia promotes glycosaminoglycan accumulation in cultured chicken embryo valves and adult murine heart valves. Thus, hypoxia maintains a primitive extracellular matrix during heart valve development and promotes extracellular matrix remodeling in adult mice, as occurs in myxomatous disease.

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Section: Discussionsupporting

confidence: 69%

Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves

Amofa

Hulin

Nakada

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…The AV leaflets were immediately processed for ex vivo culture and histology (6/9), while some were preserved in−80°C for protein isolation as fresh tissue controls (3/9). Culture of whole AV leaflets was performed as described previously (5). The leaflets were secured in 6-well plates coated with a 2 mm layer of polydimethylsiloxane (PDMS; Dow Corning, Midland, MI) using a stainless-steel insect pin inserted through the center of each leaflet and the pin tip was secured in PDMS to prevent folding of leaflets.…”

Section: Methodsmentioning

confidence: 99%

“…The leaflets were secured in 6-well plates coated with a 2 mm layer of polydimethylsiloxane (PDMS; Dow Corning, Midland, MI) using a stainless-steel insect pin inserted through the center of each leaflet and the pin tip was secured in PDMS to prevent folding of leaflets. The whole leaflets were cultured for 1 week with culture media (11) containing DMEM (5 mmol/L glucose), Ham's F12 (Hyclone, Logan, UT), 10% v/v bovine growth serum (BGS; Thermo Fisher Scientific, Waltham, MA), and 1% v/v antibiotic (Thermo Fisher Scientific) in either normoxic (20% O 2 ) or moderately hypoxic (13% O 2 ) conditions since severe hypoxia (5% O 2 ) was found to cause significant cell death in both VICs and endothelial cells in AV leaflets cultured ex vivo (5). Analysis of protein expression was compared between AVs cultured in 20 vs. 13% O 2 , while the baseline expression was derived from fresh AV controls.…”

Section: Methodsmentioning

confidence: 99%

“…Since AVs are largely avascular and oxygen (O 2 ) transfer within valves occurs via passive diffusion, the thickening of valves with aging can cause regions within AVs to turn progressively hypoxic. We recently demonstrated the extent of hypoxia within both aortic and mitral valves under static conditions (5). Additionally, hypoxia inducible factor-1 alpha (HIF1α), a marker of hypoxia, has been shown to be expressed in the calcific nodules in diseased AVs (6, 7).…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia Stimulates Synthesis of Neutrophil Gelatinase-Associated Lipocalin in Aortic Valve Disease

Swaminathan

Krishnamurthy

Sridhar

et al. 2019

Front. Cardiovasc. Med.

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Objective: Aortic valve disease is commonly found in the elderly population. It is characterized by dysregulated extracellular matrix remodeling followed by extensive microcalcification of the aortic valve and activation of valve interstitial cells. The mechanism behind these events are largely unknown. Studies have reported expression of hypoxia inducible factor-1 alpha (HIF1α) in calcific nodules in aortic valve disease, therefore we investigated the effect of hypoxia on extracellular matrix remodeling in aged aortic valves.Approach and Results: Western blotting revealed elevated expression of HIF1α and the complex of matrix metalloprotease 9 (MMP9) and neutrophil gelatinase-associated lipocalin (NGAL) in aged porcine aortic valves cultured under hypoxic conditions. Consistently, immunofluorescence staining showed co-expression of MMP9 and NGAL in the fibrosa layer of these porcine hypoxic aortic valves. Gelatinase zymography demonstrated that the activity of MMP9-NGAL complex was significantly increased in aortic valves in 13% O2 compared to 20% O2. Importantly, the presence of ectopic elastic fibers in the fibrosa of hypoxic aortic valves, also detected in human diseased aortic valves, suggests altered elastin homeostasis due to hypoxia.Conclusion: This study demonstrates that hypoxia stimulates pathological extracellular matrix remodeling via expression of NGAL and MMP9 by valve interstitial cells.

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“…Cells that populate the valves will either need to be able to function under low O 2 levels or respond to hypoxia by expression of HIF-1α, which can stimulate angiogenesis via the induction of VEGF. A similar angiogenic response occurs when valve cusps become thickened during the calcification process or in rheumatic valve disease (56,97,98).…”

Section: Importance Of Valve Shape and Designmentioning

confidence: 84%

Which Biological Properties of Heart Valves Are Relevant to Tissue Engineering?

Chester¹,

Grande‐Allen

2020

Front. Cardiovasc. Med.

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Over the last 20 years, the designs of tissue engineered heart valves have evolved considerably. An initial focus on replicating the mechanical and structural features of semilunar valves has expanded to endeavors to mimic the biological behavior of heart valve cells as well. Studies on the biology of heart valves have shown that the function and durability of native valves is underpinned by complex interactions between the valve cells, the extracellular matrix, and the mechanical environment in which heart valves function. The ability of valve interstitial cells to synthesize extracellular matrix proteins and remodeling enzymes and the protective mediators released by endothelial cells are key factors in the homeostasis of valve function. The extracellular matrix provides the mechanical strength and flexibility required for the valve to function, as well as communicating with the cells that are bound within. There are a number of regulatory mechanisms that influence valve function, which include neuronal mechanisms and the tight regulation of growth and angiogenic factors. Together, studies into valve biology have provided a blueprint for what a tissue engineered valve would need to be capable of, in order to truly match the function of the native valve. This review addresses the biological functions of heart valve cells, in addition to the influence of the cells' environment on this behavior and examines how well these functions are addressed within the current strategies for tissue engineering heart valves in vitro, in vivo, and in situ.

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Differential cell-matrix responses in hypoxia-stimulated aortic versus mitral valves

Cited by 21 publications

References 42 publications

Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves

Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves

Hypoxia Stimulates Synthesis of Neutrophil Gelatinase-Associated Lipocalin in Aortic Valve Disease

Which Biological Properties of Heart Valves Are Relevant to Tissue Engineering?

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