Changes in Perlecan Expression During Vascular Injury

Kinsella, Michael G.; Tran, Phan‐Kiet; Weiser‐Evans, Mary C.M.; Reidy, Michael A.; Majack, Richard A.; Wight, Thomas N.

doi:10.1161/01.atv.0000063109.94810.ee

Cited by 53 publications

(25 citation statements)

References 61 publications

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“…Several previous studies have shown that intact perlecan proteoglycan inhibits in vitro SMC proliferation (6,16,30). An in vivo vascular injury study has shown that perlecan accumulation attenuates neointimal SMC proliferation (11). Moreover, removal of HS from carotid intimal lesions restores the proliferative response of intimal SMCs to PDGF in organ cultures (10).…”

Section: Discussionmentioning

confidence: 99%

Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury

Gotha

Lim

Osherov

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury. Am J Physiol Heart Circ Physiol 307: H337-H345, 2014. First published May 23, 2014; doi:10.1152 doi:10. /ajpheart.00654.2013can is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2 ⌬3/⌬3 (M⌬3/⌬3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from M⌬3/⌬3 and wild-type mice. Proliferation of M⌬3/⌬3 SMC was 1.5ϫ greater than in wild type (P Ͻ 0.001), increased by addition of growth factors, and showed a 42% greater migratory response than wild-type cells to PDGF-BB (P Ͻ 0.001). In M⌬3/⌬3 SMC adhesion to fibronectin, and collagen types I and IV was significantly greater than wild type. Addition of DRL-12582, an inducer of perlecan expression, decreased proliferation and migratory response to PDGF-BB stimulation in wild-type SMC compared with M⌬3/⌬3. In an in vivo carotid artery wire injury model, the medial thickness, medial area/lumen ratio, and macrophage infiltration were significantly increased in the M⌬3/⌬3 mice, indicating a prominent role of the HS side chain in limiting vascular injury response. Mutant perlecan that lacks HS side chains had a marked reduction in the inhibition of in vitro SMC function and the in vivo arterial response to injury, indicating the critical role of HS side chains in perlecan function in the vessel wall.heparan sulfate proteoglycans; perlecan; arterial injury; smooth muscle cells PROTEOGLYCANS belong to a specific group of extracellular matrix proteins consisting of a core protein and glycosaminoglycans such as chondroitin sulfate, dermatan sulfate, heparan sulfate, or keratin sulfate (21). Proteoglycans regulate vascular smooth muscle cell (SMC) function by assembly and structure of the basement membrane, regulation of basement membrane permeability, growth factor activity, and cellular adhesion (14, 26).Perlecan is a member of the proteoglycan family that has heparan sulfate (HS) side chains, with three known HS-attachment sites in the NH 2 -terminal domain I. The effects of heparan sulfate proteoglycan (HSPG) depend on the specific sulfated form of HS produced, and its location. HS produced by SMC is known to be a potent inhibitor of SMC migration and proliferation (4,5,12). On the other hand, HS has also been crucial to the fibroblast growth factor (FGF)-induced stimulation of SMC (3, 27), as well as an enhancer of vascular endothelial growth factor (VEGF) activity (7), and cell adhesion (1). Hspg2 ⌬3/⌬3 (M⌬3/⌬3) mice, generated by deletion of exon 3 of mouse perlecan gene (Hspg2), co...

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Section: Discussionmentioning

confidence: 99%

Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury

Gotha

Lim

Osherov

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Perlecan expression and PTEN activity are associated with developmental and late postinjury decreases in SMC replication. 7,16 PTEN inactivation is associated specifically with actively dividing SMCs during early to mid stages of lesion formation. In the early stages of injury repair, SMCs proliferate in response to increased release of growth factors.…”

Section: Discussionmentioning

confidence: 99%

“…In agreement, a previous study showed proliferative responses to growth factors of intimal SMCs in late lesions is increased after heparinase treatment. 16 Additionally, heparin increases SMC-derived perlecan core protein production, which may, in turn, promote SMC growth inhibition. 7 However, we have consistently shown heparin or HS chains alone do not elicit the same degree of growth inhibition as fully sulfated perlecan, especially under serumstimulated conditions.…”

Section: Discussionmentioning

confidence: 99%

“…7,9 Decreased SMC-derived perlecan production is associated with increased SMC replication rates after vascular injury. 16 However, accumulation of perlecan in the later stages of injury repair is associated with the attenuation of neointimal SMC proliferation. Our recent studies show perlecaninduced SMC growth suppression is mediated, at least in part, through the active upregulation of focal adhesion kinase-related nonkinase (FRNK), which subsequently suppresses FAKdependent growth signals.…”

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Perlecan-Induced Suppression of Smooth Muscle Cell Proliferation Is Mediated Through Increased Activity of the Tumor Suppressor PTEN

Garl

Wenzlau

Walker

et al. 2004

Circulation Research

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Abstract-We were interested in the elucidation of the interaction between the heparan sulfate proteoglycan, perlecan, and PTEN in the regulation of vascular smooth muscle cell (SMC) growth. We verified serum-stimulated DNA synthesis, and Akt and FAK phosphorylation were significantly reduced in SMCs overexpressing wild-type PTEN. Our previous studies showed perlecan is a potent inhibitor of serum-stimulated SMC growth. We report in the present study, compared with SMCs plated on fibronectin, serum-stimulated SMCs plated on perlecan exhibited increased PTEN activity, decreased FAK and Akt activities, and high levels of p27, consistent with SMC growth arrest. Adenoviral-mediated overexpression of constitutively active Akt reversed perlecan-induced SMC growth arrest while morpholino antisense-mediated loss of endogenous PTEN resulted in increased growth and phosphorylation of FAK and Akt of SMCs on perlecan. Immunohistochemical and Western analyses of balloon-injured rat carotid artery tissues showed a transient increase in phosphoPTEN (inactive) after injury, correlating to high rates of neointimal cell replication; phosphoPTEN was largely limited to actively replicating SMCs. Similarly, in the developing rat aorta, we found increased PTEN activity associated with increased perlecan deposition and decreased SMC replication rates. However, significantly decreased PTEN activity was detected in aortas of perlecan-deficient mouse embryos, consistent with SMC hyperplasia observed in these animals, compared with E17.5 heterozygous controls that produce abundant amounts of perlecan at this developmental time point. Our data show PTEN is a potent endogenously produced inhibitor of SMC growth and increased PTEN activity mediates perlecan-induced suppression of SMC proliferation. Key Words: smooth muscle cell proliferation Ⅲ restenosis Ⅲ vascular injury Ⅲ vascular development Ⅲ basement membrane V ascular smooth muscle cells (SMCs) demonstrate high rates of replication during embryonic development significantly contributing to the maturation of the vessel wall. 1 In addition, SMCs are capable of marked increases in replication after injury to the mature vessel wall, a major component of the vessel remodeling observed in a variety of vascular pathologies. 2,3 In the absence of vascular trauma, the mature blood vessel remains a highly quiescent tissue and SMCs are resistant to stimulation by most mitogens, 2-5 suggesting the existence of active growth-suppressive mechanisms. SMCs in mature arteries are surrounded by a basement membrane matrix. 6 Our previous studies showed the accumulation of a perlecan-rich basement membrane actively inhibits SMC growth. [7][8][9][10] Perlecan, a large multidomain heparan sulfate proteoglycan, is essential for the assembly and maintenance of a functional basement membrane. 11-14 Homozygous perlecan-null mice die in utero and, important to our studies, display hyperplasia of SMC-specific ␣-actin-positive mesenchymal cells. [13][14][15] We showed perlecan expression is initiated in early fetal...

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“…• C (Kinsella et al 2003). Thereafter, they were washed out twice with the extracellular solution and used for patch-clamp experiments.…”

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confidence: 99%

Extracellular matrix proteoglycan plays a pivotal role in sensitization by low pH of mechanosensitive currents in nociceptive sensory neurones

Kubo

Katanosaka

Mizumura

2012

The Journal of Physiology

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Key points• Tissue acidosis is caused in many pathological and physiological conditions (e.g. ischaemia, inflammation and exercise) and induces pain and mechanical hyperalgesia.• An augmented mechanical response of thin-fibre afferents by low pH has been reported, but the sensitizing mechanism has not been determined.• In this study we examined whether mechanically activated (MA) currents recorded from the soma of cultured sensory neurones were augmented by low pH application.• We showed that low pH mainly sensitized MA currents of IB4-positive neurones expressing an extracellular matrix proteoglycan, versican, and this sensitization was attenuated by manipulating the extracellular matrix proteoglycan, but not by blocking intracellular signalling pathways.• These results show us a novel sensitizing mechanism involving extracellular matrix proteoglycans, which is different from currently popular sensitizing mechanisms involving intracellular signalling pathways.Abstract Ischaemia, inflammation, and exercise lead to tissue acidosis, which induces pain and mechanical hyperalgesia. Corresponding to this, enhanced thin-fibre afferent responses to mechanical stimulation have been recorded in vitro at low pH. However, knowledge about how this sensitization by low pH occurs is lacking. In this study, we found that all three types (rapidly adapting (RA), intermediately adapting and slowly adapting) of mechanically activated currents recorded with the whole cell patch-clamp method were sensitized by low pH in rat cultured dorsal root ganglion neurones. This sensitization was mainly observed in neurones positively labelled with isolectin B4 (IB4), which binds to versican, a chondroitin sulfate proteoglycan. Inhibitors of acid-sensitive channels (amiloride and capsazepine) did not block sensitization by low pH except in RA neurones, and extracellular calcium was not involved even in the sensitization of this type of neurone. A broad spectrum kinase inhibitor and a phospholipase C inhibitor (staurosporine and U73122) failed to block pH-induced sensitization in IB4-positive neurones, suggesting that these intracellular signalling pathways are not involved. Notably, both excess chondroitin sulfate in the extracellular solution and pretreatment of the neurone culture with chondroitinase ABC attenuated this low pH-induced sensitization in IB4-positive neurones. These findings suggest that a change in interaction between mechanosensitive channels and/or their auxiliary molecules and the side chain of versican on the cell surface causes this sensitization, at least in IB4-positive neurones. This report proposes a novel mechanism for sensitization that involves extracellular proteoglycans (versican).

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Changes in Perlecan Expression During Vascular Injury

Cited by 53 publications

References 61 publications

Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury

Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury

Perlecan-Induced Suppression of Smooth Muscle Cell Proliferation Is Mediated Through Increased Activity of the Tumor Suppressor PTEN

Extracellular matrix proteoglycan plays a pivotal role in sensitization by low pH of mechanosensitive currents in nociceptive sensory neurones

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