Dual Structural and Functional Phenotypes of the Porcine Aortic Valve Interstitial Population: Characteristics of the Leaflet Myofibroblast

Messier, Robert H.; Bass, Barbara L.; Aly, Hamdy M.; Jones, Janice L.; Domkowski, Patrick W.; Wallace, Robert B.; Hopkins, Richard A.

doi:10.1006/jsre.1994.1102

Cited by 167 publications

(133 citation statements)

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“…HAVICs were isolated following a modification of a previously described method (16). Valve leaflets were rinsed in Earle's balanced salt solution (EBSS) and then digested in collagenase (2.5 mg/ml in M199 medium) for 30 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis

Meng

Ao²,

Song³

et al. 2008

American Journal of Physiology-Cell Physiology

150

206

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aortic valve stenosis is the most common indication for surgical valve replacement. Inflammation appears to be one of the mechanisms involved in aortic valve calcification, and valve interstitial cells seem to contribute to that process. Although Toll-like receptors (TLRs) play an important role in the cellular inflammatory response, it is unknown whether human aortic valve interstitial cells (HAVICs) express functional TLRs. We examined the expression of TLR2 and TLR4 in human aortic valve leaflets and in isolated HAVICs and analyzed the response of cultured HAVICs to the TLR2 and TLR4 agonists peptidoglycan (PGN) and LPS. Abundant TLR2 and TLR4 proteins were found in human aortic valve leaflets and in isolated HAVICs, and both receptors were detected in the membrane and cytoplasm of cultured HAVICs. Stimulation by either PGN or LPS resulted in the activation of the NF-B signaling pathway and the production of multiple proinflammatory mediators, including IL-6, IL-8, and ICAM-1. In addition, stimulation by either PGN or LPS upregulated the expression of bone morphogenetic protein-2 (BMP-2) and Runx2, factors associated with osteogenesis. This study demonstrates for the first time that HAVICs express TLR2 and TLR4 and that stimulation of HAVICs by PGN or LPS induces the expression of proinflammatory mediators and the upregulation of osteogenesis-associated factors. These results suggest that TLR2 and TLR4 may play a role in aortic valve inflammation and stenosis. cytokines; intracellular cell adhesion molecule-1; bone morphogenetic protein-2; Runx2

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Section: Methodsmentioning

confidence: 99%

Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis

Meng

Ao²,

Song³

et al. 2008

American Journal of Physiology-Cell Physiology

150

206

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“…Within each of the four layers of the MV leaflet tissues there resides a heterogeneous population of interstitial cells that maintain the structural integrity of the MV tissue via protein biosynthesis and enzymatic degradation (51)(52)(53)(54). Among all valve interstitial cells (VICs), mitral valve interstitial cells (MVICs) have the characteristics of both fibroblasts and smooth muscle cells.…”

Section: Relation To Cellular Deformation and Strain-induced Tissue Fmentioning

confidence: 99%

On the Presence of Affine Fibril and Fiber Kinematics in the Mitral Valve Anterior Leaflet

Lee

Zhang

Liao

et al. 2015

Biophysical Journal

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In this study, we evaluated the hypothesis that the constituent fibers follow an affine deformation kinematic model for planar collagenous tissues. Results from two experimental datasets were utilized, taken at two scales (nanometer and micrometer), using mitral valve anterior leaflet (MVAL) tissues as the representative tissue. We simulated MVAL collagen fiber network as an ensemble of undulated fibers under a generalized two-dimensional deformation state, by representing the collagen fibrils based on a planar sinusoidally shaped geometric model. The proposed approach accounted for collagen fibril amplitude, crimp period, and rotation with applied macroscopic tissue-level deformation. When compared to the small angle x-ray scattering measurements, the model fit the data well, with an r 2 ¼ 0.976. This important finding suggests that, at the homogenized tissue-level scale of~1 mm, the collagen fiber network in the MVAL deforms according to an affine kinematics model. Moreover, with respect to understanding its function, affine kinematics suggests that the constituent fibers are largely noninteracting and deform in accordance with the bulk tissue. It also suggests that the collagen fibrils are tightly bounded and deform as a single fiber-level unit. This greatly simplifies the modeling efforts at the tissue and organ levels, because affine kinematics allows a straightforward connection between the macroscopic and local fiber strains. It also suggests that the collagen and elastin fiber networks act independently of each other, with the collagen and elastin forming long fiber networks that allow for free rotations. Such freedom of rotation can greatly facilitate the observed high degree of mechanical anisotropy in the MVAL and other heart valves, which is essential to heart valve function. These apparently novel findings support modeling efforts directed toward improving our fundamental understanding of tissue biomechanics in healthy and diseased conditions.

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“…VICs are a dynamic and heterogeneous population of cells exhibiting phenotypes of smooth muscle cells (SMCs), fibroblasts, and myofibroblasts (7,41,55) where myofibroblasts are cells that display properties of both fibro- blasts and SMCs (32,33). In healthy adults, fibroblast-like cells are the predominant cell type in valve tissues, with the few or no myofibroblasts (32,46).…”

Section: Discussionmentioning

confidence: 99%

Pregnancy-induced remodeling of heart valves

Pierlot

Moeller

Lee

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves. HEART VALVES ARE COMPLEX and dynamic biological structures. They play important roles toward efficient cardiac pumping, ensuring unidirectional blood flow while opening and closing 3 billion times in a lifetime. The extent and the mechanisms via which the valves may adapt to changing loading conditions in either physiology or pathology remain unclear. Many investigations of valve adaptation have focused on physiological development (8,20,(51)(52)(53) or pathological conditions such as left ventricular (LV) dysfunction (10), mitral valve regurgitation (58), myxomatous degeneration (19), or heart failure (17). Recent studies from our laboratory, however, have demonstrated the capacity of maternal heart valve leaflets to remodel under the altered hemodynamics of pregnancy, a nonpathological condition (38,39,60). Pregnancy is accompanied by an increase in blood volume and cardiac output of ϳ50%, as the maternal circulation accommodates the developing fetoplacental unit. This volume overload produces cardiac enlargement (21, 45, 60) with expansion of valve orifices (areas increasing from 12-53% in humans; see Refs. 9 and 43). These changes in geometry then elevate...

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Dual Structural and Functional Phenotypes of the Porcine Aortic Valve Interstitial Population: Characteristics of the Leaflet Myofibroblast

Cited by 167 publications

References 0 publications

Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis

Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis

On the Presence of Affine Fibril and Fiber Kinematics in the Mitral Valve Anterior Leaflet

Pregnancy-induced remodeling of heart valves

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