Matrix metalloproteinases in vascular physiology and disease

Siefert, Suzanne A.; Sarkar, Rajabrata

doi:10.1258/vasc.2011.201202

Cited by 141 publications

(112 citation statements)

References 56 publications

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“…Normal physiological levels of shear stress maintain endothelial cells in a quiescent state by inducing cell cycle arrest (Lin et al, 2000) and strengthening tight junctions (Lin et al, 2000). For sprouting to occur, however, endothelial cells must re-enter the cell cycle (Bai et al, 2014), loosen their attachment to neighbouring cells (Lampugnani and Dejana, 2007), degrade the local basement membrane (Siefert and Sarkar, 2012) and then invade the tissue. Although shear stress is known to affect many of these pathways, very little is known about the effects of shear stress on angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Flow dynamics control the location of sprouting and direct elongation during developmental angiogenesis

2015

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Angiogenesis is tightly controlled by a number of signalling pathways. Although our understanding of the molecular mechanisms involved in angiogenesis has rapidly increased, the role that biomechanical signals play in this process is understudied. We recently developed a technique to simultaneously analyse flow dynamics and vascular remodelling by time-lapse microscopy in the capillary plexus of avian embryos and used this to study the hemodynamic environment present during angiogenic sprouting. We found that sprouts always form from a vessel at lower pressure towards a vessel at higher pressure, and that sprouts form at the location of a shear stress minimum, but avoid locations where two blood streams merge even if this point is at a lower level of shear stress than the sprouting location. Using these parameters, we were able to successfully predict sprout location in quail embryos. We also found that the pressure difference between two vessels is permissive to elongation, and that sprouts will either change direction or regress if the pressure difference becomes negative. Furthermore, the sprout elongation rate is proportional to the pressure difference between the two vessels. Our results show that flow dynamics are predictive of the location of sprout formation in perfused vascular networks and that pressure differences across the interstitium can guide sprout elongation.

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Section: Introductionmentioning

confidence: 99%

Flow dynamics control the location of sprouting and direct elongation during developmental angiogenesis

2015

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“…They are also involved in modulating the activity of signaling molecules and play important roles in both normal physiology and pathological processes including neovascularization and tumor metastasis. [2][3][4][5] As such, MMPs are important potential targets for controlling such processes and in treating of a variety of pathological conditions. Matrix metalloproteinase 14 (also known as membrane type 1 MMP, MT1-MMP) in particular is involved in many processes including wound healing, angiogenesis, inflammation, and cancer invasion and metastasis.…”

mentioning

confidence: 99%

Evidence for the involvement of MMP14 in MMP2 processing and recruitment in exosomes of corneal fibroblasts

Han¹,

Dugas-Ford²,

Seiki³

et al. 2014

Investigative Ophthalmology & Visual Science

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PURPOSE. Matrix metalloproteinase (MMP) 14 has been shown to promote angiogenesis, but the underlying mechanisms are poorly understood. In this study, we investigated exosomal transport of MMP14 and its target, MMP2, from corneal fibroblasts to vascular endothelial cells as a possible mechanism governing MMP14 activity in corneal angiogenesis. METHODS.We isolated MMP14-containing exosomes from corneal fibroblasts by sucrose density gradient and evaluated exosome content and purity by Western blot analysis. We then investigated exosome transport in vitro from corneal fibroblasts to two populations of vascular endothelial cells, human umbilical vein endothelial cells (HUVECs) and calf pulmonary artery endothelial cells (CPAECs). Western blot analysis and gelatin zymography were used to determine levels of MMP14 and MMP2, respectively, in exosomal fractions derived from cultured wild-type, MMP14 enzymatic domain-deficient (MMP14Dexon4), and MMP14-null corneal fibroblasts.RESULTS. Matrix metalloproteinase 14-containing exosomes isolated from corneal fibroblasts were readily taken up in vitro by HUVECs and CPAECs. We found that MMP14 was enriched in exosomal fractions of cultured corneal fibroblasts. Moreover, loss of the MMP14 enzymatic domain resulted in accumulation of pro-MMP2 protein in exosomes, whereas MMP2 was nearly undetectable in exosomes of MMP14-null fibroblasts. CONCLUSIONS.Our results indicate that exosomes secreted by corneal fibroblasts can transport proteins, including MMP14, to vascular endothelial cells. In addition, recruitment of MMP2 into corneal fibroblast exosomes is an active process that depends, at least in part, on the presence of MMP14. The role of exosomal MMP14 transport in corneal angiogenesis has important implications for therapeutic applications targeting angiogenic processes in the cornea.

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“…Control of MMP activity occurs at several levels: transcription, activation of the precursor zymogen, and inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases). Without regulation, active MMPs can cause extensive ECM remodeling and result in a spectrum of pathological conditions, including arthritis, cancer, atherosclerosis, and fibrosis (21,24,27). However, the absence of MMP activity results in unresolved repair in bone (16), stalled development (14), and impaired wound healing (reviewed in Ref.…”

mentioning

confidence: 99%

Matrix metalloproteinase 13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration

Lei

Leong

Smith

et al. 2013

American Journal of Physiology-Cell Physiology

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Lei H, Leong D, Smith LR, Barton ER. Matrix metalloproteinase 13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration. Am J Physiol Cell Physiol 305: C529-C538, 2013. First published June 12, 2013 doi:10.1152/ajpcell.00051.2013.-Efficient skeletal muscle repair and regeneration require coordinated remodeling of the extracellular matrix (ECM). Previous reports have indicated that matrix metalloproteinases (MMPs) play the pivotal role in ECM remodeling during muscle regeneration. The goal of the current study was to determine if the interstitial collagenase MMP-13 was involved in the muscle repair process. Using intramuscular cardiotoxin injections to induce acute muscle injury, we found that MMP-13 expression and activity transiently increased during the regeneration process. In addition, in muscles from mdx mice, which exhibit chronic injury, MMP-13 expression and protein levels were elevated. In differentiating C2C12 cells, a murine myoblast cell line, Mmp13 expression was most pronounced after myoblast fusion and during myotube formation. Using pharmacological inhibition of MMP-13 to test whether MMP-13 activity is necessary for the proliferation, differentiation, migration, and fusion of C2C12 cells, we found a dramatic blockade of myoblast migration, as well as a delay in differentiation. In contrast, C2C12 cells with stable overexpression of MMP-13 showed enhanced migration, without affecting myoblast maturation. Taken together, these results support a primary role for MMP-13 in myoblast migration that leads to secondary effects on differentiation.collagenase; matrix metalloproteinase; muscle repair; myoblast maturation

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Matrix metalloproteinases in vascular physiology and disease

Cited by 141 publications

References 56 publications

Flow dynamics control the location of sprouting and direct elongation during developmental angiogenesis

Flow dynamics control the location of sprouting and direct elongation during developmental angiogenesis

Evidence for the involvement of MMP14 in MMP2 processing and recruitment in exosomes of corneal fibroblasts

Matrix metalloproteinase 13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration

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