superkuhni.by/js Matrix fragments may also modulate fibroblast and vascular cell phenotype Endostatin, a kDa fragment of collagen XVIII, exerts potent angiostatic actions 45 and stimulates fibroblast proliferation MMP9-mediated cleavage of collagen IV also generates fragments with angiostatic properties, such as tumstatin The role of endogenous matrix fragments in regulation of fibrogenic and angiogenic responses following myocardial infarction remains poorly understood. The plasma-derived provisional matrix regulates the inflammatory response. Degradation of the original cardiac matrix network in the infarcted myocardium is accompanied by formation of a provisional matrix Rapid induction of VEGF in the infarcted heart increases vascular permeability 48 , leading to extravasation of plasma fibrinogen and fibronectin and generating a complex and dynamic fibrin-based matrix network 39 , The role of the provisional matrix in regulating cardiac repair remains poorly understood; current concepts are predominantly based on extrapolation of findings from studies that investigate reparative responses in other systems.
In addition to its hemostatic role, the provisional matrix may serve as a scaffold for migrating inflammatory cells and support proliferating endothelial cells and fibroblasts Components of the provisional matrix interact with migrating cells through cell surface integrins 51 and may also transduce signaling cascades that modulate immune cell phenotype and gene expression In vitro, fibrinogen stimulates macrophage-derived chemokine secretion through TLR4 activation In a mouse model of reperfused myocardial infarction, fibrin-mediated interactions contributed to early injury by accentuating the inflammatory response Treatment with a naturally occurring peptide that competes with the fibrin fragment N-terminal disulfide knot-II an analog of the fibrin E1 fragment for binding to vascular endothelial cadherin reduced infarct size, attenuating leukocyte infiltration in the ischemic myocardium in both rodent and large animal models 54 , Unfortunately, the effects of the peptide in a small clinical trial were much less impressive.
Peptide administration in patients with ST-elevation myocardial infarction STEMI did not affect the size of the infarct assessed through magnetic resonance imaging and did not reduce serum troponin I levels The provisional matrix may also play an important role in the transition to the proliferative phase of cardiac repair by serving as a reservoir for cytokines and growth factors. Dynamic changes in the composition of the ECM may contribute to the reparative cellular responses during the proliferative phase of cardiac repair Figure 2. Clearance of matrix fragments by phagocytes may activate antiinflammatory signals, suppressing recruitment of proinflammatory leukocytes.
Lysis of the plasma-derived provisional matrix is followed by organization of a cell-derived matrix network, comprising cellular fibronectin, hyaluronan, proteoglycans, and a wide range of matricellular macromolecules 39 that transduce growth factor signals to reparative cells The dynamic alterations of the ECM during the proliferative phase provide essential signals for conversion of fibroblasts into myofibroblasts and may activate angiogenic pathways necessary for neovessel formation, thus supplying the metabolically active wound with oxygen and nutrients The role of the cell-derived provisional matrix in cardiac repair.
A During the proliferative phase of cardiac repair, fibroblasts and macrophages contribute to the formation of a cell-derived provisional matrix, enriched with a wide range of matricellular macromolecules that do not serve a primary structural role, but modulate cellular phenotype and function. Specific matricellular proteins have been reported as regulating inflammation, participating in fibrogenic and angiogenic responses, modulating cardiomyocyte survival, and contributing to assembly of the structural matrix. B Matricellular proteins may be critical in spatial and temporal regulation of growth factor signaling.
Spatially and temporally restricted induction of matricellular proteins regulates growth factor signaling, preventing expansion of profibrotic responses beyond the infarcted area, despite possible diffusion of the soluble mediators in viable segments. Reproduced with permission from Circulation GAGs, glycosaminoglycosans. Fibrin network clearance and cell-derived provisional matrix formation.
Mice lacking plasminogen exhibited markedly attenuated recruitment of inflammatory leukocytes in the infarct and impaired granulation tissue formation Lysis of the fibrin-based matrix is followed by secretion of cellular fibronectin by fibroblasts and macrophages 62 , 63 and by deposition of hyaluronan and versican, forming a network of cell-derived provisional matrix that is later enriched with a wide range of matricellular macromolecules During the proliferative phase of healing, the highly dynamic matrix becomes a regulatory center that transduces essential signals to activate reparative fibroblasts and vascular cells.
Components of the provisional matrix regulate fibroblast activation. In vivo, ED-A fibronectin loss attenuates myofibroblast transdifferentiation in healing myocardial infarction Hyaluronan and versican have also been implicated in myofibroblast conversion. In vivo, loss of CD44, the main receptor for haluronan, impaired collagen synthesis in infarct fibroblasts Versican loss in dermal fibroblasts attenuated myofibroblast conversion Although versican is upregulated in healing myocardial infarcts 69 , its in vivo role in transdifferentiation of injury-site cardiac myofibroblasts has not been directly documented.
Induction of matricellular proteins. During the proliferative phase of infarct healing, the cardiac ECM is enriched through the deposition of a wide range of structurally diverse matricellular proteins that do not serve a direct structural role, but act contextually by regulating cytokine and growth factor responses and modulating cell phenotype and function 70 , Several other proteins including members of the galectin and syndecan family, fibulins, osteoglycin, and other small leucine-rich proteoglycans have been found to exert matricellular actions as part of their broader spectrum of functional properties.
Most members of the matricellular family show low expression in the normal myocardium, but are markedly upregulated following myocardial injury.
In healing infarctions, angiotensin and growth factors stimulate de novo synthesis and secretion of matricellular proteins in fibroblasts or immune or vascular cells 39 , 73 , Once secreted into the interstitium, matricellular macromolecules bind to the structural matrix and transduce signaling cascades through ligation of cell surface receptors or contribute to activation of cytokines, growth factors, and proteases in the pericellular space. An overview of the pattern of regulation, function, targets, and mechanisms of action of the matricellular proteins discussed below is given in Table 1.
Several prototypical members of the matricellular family are markedly upregulated following myocardial infarction and protect the myocardium from adverse remodeling 75 — Localized induction of TSP-1 in the infarct border zone may form a barrier that prevents expansion of inflammation in viable myocardial areas through local activation of antiinflammatory signals Osteopontin may protect from left ventricular dilation by promoting matrix deposition in the infarcted region SPARC has been shown to protect from cardiac rupture and postinfarction heart failure by contributing to collagen maturation through activation of growth factor signaling Periostin serves as a crucial regulator of fibroblast recruitment and activity 81 and prevents cardiac rupture 81 , 82 , promoting formation of an organized collagen-based scar.
Although each matricellular protein has a unique functional profile, several unifying themes have emerged regarding their actions in the infarcted heart. First, the strikingly selective localization of prototypical members of the family in the infarct border zone and their regulatory effects on the activity of soluble mediators highlight their role in spatial regulation of cellular responses.
Secreted growth factors and cytokines can diffuse beyond the infarct zone; the requirement for matricellular proteins in activating growth factor—mediated responses may serve to localize inflammatory and fibrotic responses within areas of injury. Second, transient expression of matricellular proteins during the proliferative phase of healing ensures temporal regulation of growth factor responses.
Clearance of matricellular proteins from the infarcted area may serve as an important STOP signal, preventing uncontrolled fibrosis following injury. In vitro studies have demonstrated that alternatively activated macrophages internalize SPARC through the scavenger receptor stabilin 1 However, the potential role of immune cell subsets in endocytosis and degradation of matricellular proteins in vivo has not been tested. Third, repair of the infarcted myocardium is dependent on a highly dynamic microenvironment that promotes cellular plasticity.
In response to microenvironmental cues, interstitial cells exhibit phenotypic changes 84 — 86 , leading to transitions from inflammatory to reparative phenotypes Through their transient induction and incorporation into the matrix, matricellular proteins may play a critical role in regulating cell differentiation, contributing to the cellular plasticity observed in healing tissues through direct actions and via modulation of growth factor—mediated pathways. Scar maturation is associated with ECM crosslinking in the infarct zone and with a marked reduction in myofibroblast density Descriptive studies have suggested that apoptosis may be involved in elimination of granulation tissue cells from the infarct 89 , 90 ; however, the mechanisms responsible for cell-specific activation of a proapoptotic program in the late phase of infarct healing have not been investigated.
Acquisition of a quiescent phenotype may precede apoptosis of infarct myofibroblasts. Formation of a mature crosslinked matrix and clearance of matricellular proteins may play an important role in regulating fibroblast deactivation in the healing infarct 91 — It is tempting to hypothesize that endogenous mechanisms that restrain matricellular actions protect the infarcted heart from progressive fibrosis, depriving fibroblasts of the prolonged actions of growth factor—mediated signals.
Vascular cells may also respond to the mature ECM environment. ECM proteins have been implicated in modulation of endothelial-pericyte interactions in vitro and in vivo 95 , 96 , but whether such effects play a role in maturation of infarct microvessels remains unknown. It should be emphasized that in the presence of a large infarction with significant hemodynamic consequences, viable noninfarcted myocardium also exhibits slowly progressive interstitial fibrosis related to the pathophysiologic effects of pressure and volume loads.
Inflammation and fibrosis are suppressed in the healing infarct, leading to formation of a mature collagen-based scar, but in the viable noninfarcted zone, increased wall stress may locally activate macrophages and fibroblasts, triggering chronic progressive expansion of the cardiac interstitial matrix 97 , Pressure and volume overload are critically implicated in the pathogenesis of heart failure in a wide variety of cardiac conditions. Left ventricular pressure overload is the critical pathophysiologic companion of the cardiomyopathy induced by systemic hypertension and aortic stenosis.
On the other hand, valvular regurgitant lesions such as aortic and mitral insufficiency cause cardiac remodeling and heart failure by subjecting the heart to volume overload.
Moreover, both pressure and volume loads contribute to the pathophysiology of postinfarction remodeling. Pressure and volume overload have distinct effects on the cardiac ECM that may account for their consequences on ventricular geometry and function.
ECM in the pressure-overloaded myocardium. In both experimental models and in human patients, cardiac pressure overload causes early hypertrophic remodeling and diastolic dysfunction, followed by decompensation, chamber dilation, and development of systolic heart failure.
Pressure overload is associated with profound and dynamic changes in the composition of the ECM; these changes regulate geometry and function, not only by affecting the mechanical properties of the ventricle, but also by modulating cellular responses. Show all. Pages Masoud, Waleed G. Show next xx. Recommended for you. Jugdutt Naranjan S.
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