Basement membrane assembly, stability and activities observed through a developmental lens

Yurchenco, Peter D.; Amenta, Peter S.; Patton, Bruce L.

doi:10.1016/j.matbio.2003.10.006

Cited by 340 publications

(325 citation statements)

References 159 publications

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“…44,45 Healthy ECs secrete low amounts of fibronectin and collagen type IV, while collagen type I and type III are nearly absent and appear only after fibrosis has been established. [44][45][46][47] We demonstrated that ECs exposed to oxidative stress overexpress the ECM proteins fibronectin and collagen type III, suggesting that oxidative stress induces abnormal ECM overload in ECs. Because ECM proteins are molecular bridges by which bacteria adhere and invade host cells, the oxidative stress-induced ECM overexpression could represent a mechanism to generate bacterial pathogenesis and enhance the inflammatory response.…”

Section: Discussionmentioning

confidence: 82%

“…The increase in ECM proteins during EndMT alters EC function because it affects the interaction between ligands and membrane receptors, protein turnover, and protein internalization. 34,36,37,[41][42][43][44][45][46][47] In addition, increased cell migration is a major distinctive feature of myofibroblasts. Because EndMT is a cellular mechanism for the conversion of polarized ECs into motile mesenchymal cells, this process is also characterized by the acquisition of migratory features.…”

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confidence: 99%

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Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

120

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

120

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“…They are laminin-binding proteins, important for joining together laminin and type IV collagen networks and for the proper assembly of various BMs. 38 Two nidogens are similar in structure and have a largely overlapping repertoire of protein interactions and, possibly, functions. 24,38 In these cases, mostly nidogen-2 was found around INTACS channels; nidogen-1 showed significantly weaker staining (Fig.…”

Section: Discussionmentioning

confidence: 99%

Alterations of Extracellular Matrix Components and Proteinases in Human Corneal Buttons With INTACS for Post-Laser In Situ Keratomileusis Keratectasia and Keratoconus

Maguen¹,

Rabinowitz²,

Regev³

et al. 2008

Cornea

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Purpose-To perform an immunohistochemical evaluation of corneas with INTACS for post-laser in situ keratomileusis (LASIK) keratectasia and keratoconus, obtained after corneal transplantation.Methods-Corneas from 1 patient with INTACS for post-LASIK keratectasia and 2 patients with INTACS for keratoconus were obtained within 3 hours after penetrating keratoplasty, and cryostat sections were analyzed by immunostaining for 35 extracellular matrix (ECM) components and proteinases.Results-In the stroma of all corneas next to an INTACS implant, ECM components typically associated with fibrosis were observed. These included tenascin-C, fibrillin-1, and types III, IV (α1/ α2 chains), and XIV collagen. Also, significant deposition of perlecan, nidogen-2, and cellular fibronectin was revealed in the same locations. The keratoconus cases displayed typical Bowman layer breaks and subepithelial fibrosis with deposition of various ECM components. In all cases, some keratocytes around INTACS were positive for specific proteinases associated with stromal remodeling, including cathepsins F and H, matrix metalloproteinase (MMP)-1, MMP-3, and MMP-10. Staining for MMP-7 was variable; MMP-2 and MMP-9 were mostly negative. Patterns of type IV collagen α3, α4, and α6 chains; types VI and VIII collagen;α4, α5,β1, β2, and γ1 laminin chains; vitronectin; thrombospondin-1; urokinase; EMMPRIN; and cathepsins B and L were unchanged around INTACS in all 3 cases compared with normal. Recently, INTACS has acquired new interest as an alternative treatment of keratoconus. [5][6][7][8][9][10] The rationale is that INTACS not only flattens the central cornea but also corrects some of the astigmatic component. The corneal profile becomes more symmetrical, usually allowing better correction with glasses and contact lenses. Given that, for these patients, the alternative would be penetrating keratoplasty, INTACS may delay the need for this option. 10,11 Midstromal semicircular channels for INTACS ring insertion are created by a mechanical system with a blunt spiral device. 1,12,13 Despite the streamlined mechanistic procedure, attempts were made to improve control over the depth and shape of the channels. A femtosecond laser mounted on a delivery system capable of creating an intrastromal pattern of virtually any shape was recently used to create channels for INTACS insertion. 10 This method may be technically easier and more precise, reflecting better final outcomes. Conclusions-AbnormalKeratectasia is a rare but serious complication of laser vision correction of any refractive errors. It occurs mostly after LASIK but was also described after surface excimer laser ablation (photorefractive keratectomy). 14-16 It involves severe refractive changes mostly occurring several years after the surgery, which are caused by thinning and sagging of the corneal profile, similar to keratoconus.The etiology of this complication remains uncertain. In some cases, preexisting forme fruste keratoconus was documented. 17,18 Other cases could be caused by a me...

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“…BMs are a composite of several glycoproteins and proteoglycans in which two networks, formed by laminin and type IV collagen, are thought to be the basic intermingling structures (22). Laminin, like type IV collagen, is capable of self-assembly, and absence of the laminin ␤1 (23) or ␥1 (24) chain leads to death within 1 day of implantation, at E5.5.…”

Section: Discussionmentioning

confidence: 99%

Premature aggregation of type IV collagen and early lethality in lysyl hydroxylase 3 null mice

Rautavuoma

Takaluoma

Sormunen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

102

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Collagens carry hydroxylysine residues that act as attachment sites for carbohydrate units and are important for the stability of crosslinks but have been regarded as nonessential for vertebrate survival. We generated mice with targeted inactivation of the gene for one of the three lysyl hydroxylase isoenzymes, LH3. The null embryos developed seemingly normally until embryonic day 8.5, but development was then retarded, with death around embryonic day 9.5. Electron microscopy (EM) revealed fragmentation of basement membranes (BMs), and immuno-EM detected type IV collagen within the dilated endoplasmic reticulum and in extracellular aggregates, but the typical BM staining was absent. Amorphous intracellular and extracellular particles were also seen by collagen IV immunofluorescence. SDS͞PAGE analysis demonstrated increased mobilities of the type IV collagen chains, consistent with the absence of hydroxylysine residues and carbohydrates linked to them. These results demonstrate that LH3 is indispensable for biosynthesis of type IV collagen and for BM stability during early development and that loss of LH3's functions leads to embryonic lethality. We propose that the premature aggregation of collagen IV is due to the absence of the hydroxylysine-linked carbohydrates, which thus play an essential role in its supramolecular assembly. L ysyl hydroxylase (LH, EC 1.14.11.4, Plod) catalyzes the hydroxylation of lysine residues in -X-Lys-Gly-triplets in collagens and other proteins with collagen-like sequences (1). The hydroxylysine residues formed have two important functions: (i) they serve as attachment sites for carbohydrates, either monosaccharide galactose or disaccharide glucosylgalactose, and (ii) they have an important role in the stabilization of intermolecular collagen crosslinks that provide tensile strength and mechanical stability for the collagen fibrils. The extent of lysine hydroxylation and hydroxylysine glycosylation varies between collagen types. Nearly 90% of all lysines are hydroxylated and hydroxylysines glycosylated in types IV and VI collagen, whereas Ͻ20% of the lysines are hydroxylated in type III collagen (2). The functions of the hydroxylysine-linked carbohydrates are poorly understood, but in the case of fibril-forming collagens, they are thought to regulate the formation and morphology of the fibrils (1, 3).Three human LH isoenzymes have been identified (1, 4-6). Mutations in the LH1 gene lead to the kyphoscoliotic type of Ehlers-Danlos syndrome, which is characterized by scoliosis, joint laxity, skin fragility, ocular manifestations, and severe muscle hypotonia (7-9). Mutations in the LH2 gene have recently been reported in two families with Bruck syndrome, which is characterized by fragile bones, joint contractures, scoliosis, and osteoporosis (10).No mutations have been characterized in the gene for the isoenzyme LH3, and its in vivo functions have not yet been elucidated. This protein differs from the other two lysyl hydroxylase isoenzymes in that it also possesses relatively low levels...

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Basement membrane assembly, stability and activities observed through a developmental lens

Cited by 340 publications

References 159 publications

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Alterations of Extracellular Matrix Components and Proteinases in Human Corneal Buttons With INTACS for Post-Laser In Situ Keratomileusis Keratectasia and Keratoconus

Premature aggregation of type IV collagen and early lethality in lysyl hydroxylase 3 null mice

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