Regulation of Discoidin Domain Receptor 2 by Cyclic Mechanical Stretch in Cultured Rat Vascular Smooth Muscle Cells

Shyu, Kou Gi; Chao, Ya Meng; Wang, Bao Wei; Kuan, Peiliang

doi:10.1161/01.hyp.0000175811.79863.e2

Cited by 48 publications

(39 citation statements)

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“…The increased cyclic mechanical stretch in hypertension has been shown to play an important role in VSMC proliferation (19). We hypothesized that cyclic stretch may modulate VSMC proliferation by inducing the expression of emerin and lamin A/C.…”

Section: Resultsmentioning

confidence: 97%

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Yao

Huang

et al. 2016

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

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Cyclic stretch is an important inducer of vascular smooth muscle cell (VSMC) proliferation, which is crucial in vascular remodeling during hypertension. However, the molecular mechanism remains unclear. We studied the effects of emerin and lamin A/C, two important nuclear envelope proteins, on VSMC proliferation in hypertension and the underlying mechano-mechanisms. In common carotid artery of hypertensive rats in vivo and in cultured cells subjected to high (15%) cyclic stretch in vitro, VSMC proliferation was increased significantly, and the expression of emerin and lamin A/C was repressed compared with normotensive or normal (5%) cyclic stretch controls. Using targeted siRNA to mimic the repressed expression of emerin or lamin A/C induced by 15% stretch, we found that VSMC proliferation was enhanced under static and 5%-stretch conditions. Overexpression of emerin or lamin A/C reversed VSMC proliferation induced by 15% stretch. Hence, emerin and lamin A/C play critical roles in suppressing VSMC hyperproliferation induced by hyperstretch. ChIP-on-chip and MOTIF analyses showed that the DNAs binding with emerin contain three transcription factor motifs: CCNGGA, CCMGCC, and ABTTCCG; DNAs binding with lamin A/C contain the motifs CVGGAA, GCCGCYGC, and DAAGAAA. Protein/DNA array proved that altered emerin or lamin A/C expression modulated the activation of various transcription factors. Furthermore, accelerating local expression of emerin or lamin A/C reversed cell proliferation in the carotid artery of hypertensive rats in vivo. Our findings establish the pathogenetic role of emerin and lamin A/C repression in stretch-induced VSMC proliferation and suggest mechanobiological mechanism underlying this process that involves the sequencespecific binding of emerin and lamin A/C to specific transcription factor motifs.T he cyclic stretch caused by the rhythmical distention and relaxation of the arterial wall during the cardiac cycle is an important factor in the regulation of vascular modeling and remodeling (1, 2). There is growing evidence that mechanical cyclic stretch modulates the functions (e.g., apoptosis, proliferation, and migration) of vascular smooth muscle cells (VSMCs) in the media of the arterial wall (2) and that chronically elevated cyclic stretch stimulates VSMC functions to mediate vascular remodeling during hypertension (3, 4).It has been shown that there are various mechano-sensors in the vascular cell membrane, including lipids (5), glycocalyx (6), and proteins such as integrins (7), G proteins and G protein-coupled receptors (8), receptor tyrosine kinase (9), and Ca 2+ channel (10) and intercellular junction proteins (2, 11). In recent years, it has been suggested that nuclear envelope (NE) proteins, a hallmark of eukaryotic cells, participate in the mechano-transduction networks. Our previous proteomic analysis revealed that lamin A/C, one kind of NE protein, is mechano-responsive and may contribute to the shear stress-induced proliferation and migration of VSMCs (12). Recently, Swift et al. (13) ...

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Section: Resultsmentioning

confidence: 97%

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Yao

Huang

et al. 2016

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

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“…We have demonstrated previously that DDR2 expression is regulated by cyclic stretch of VSMCs mediated by increases in transforming growth factor (TGF)-␤ 1 and angiotensin II production. 7 Both TGF-␤1 and angiotensin II play important roles in the atherosclerosis. These findings clearly indicate that hemodynamic forces can play a significant role in the modulation of DDR2 expression of VSMCs.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that stretching of VSMCs in vitro resulted in upregulation of DDR2 expression. 7 In this study we hypothesize that DDR2 plays an important role in vascular injury in vivo. …”

mentioning

confidence: 89%

“…VSMCs cultured on the flexible membrane base were subjected to cyclic stretch produced by Flexcell FX-2000 strain unit (Flexcell International Co) and by vacuum to 20% of maximum elongation, at 60 cycles/min as described previously. 7 VSMCs were transfected with 800 ng DDR2 siRNA oligonucleotide (Dharmacon Inc). VSMCs were transfected with siRNA oligonucleotides using Effectene Transfection Reagent according to the manufacture's instruction (Qiagen Inc).…”

Section: Vascular Smooth Muscle Cell Culturementioning

confidence: 99%

See 1 more Smart Citation

RNA Interference for Discoidin Domain Receptor 2 Attenuates Neointimal Formation in Balloon Injured Rat Carotid Artery

Shyu¹,

Wang

Kuan

et al. 2008

ATVB

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Objectives-Discoidin domain receptor 2 (DDR2) plays potential roles in the regulation of collagen turnover mediated by smooth muscle cells (SMCs) in atherosclerosis. Little is known about the function of DDR2 in vascular system. We investigated whether inhibition of DDR2 by small interfering RNA (siRNA) can reduce neointimal formation after arterial injury. Key Words: discoidin domain receptor 2 Ⅲ smooth muscle cell Ⅲ RNA interference Ⅲ vascular injury D evelopment of neointimal thickening is the major cause of atherosclerosis and restensois. Smooth muscle cells (SMCs) are the predominant cell types in the media of blood vessel walls and contribute to neointimal formation after arterial injury. After arterial injury, SMCs synthesize collagens, 1,2 which act as important signaling molecule regulating SMC responses to arterial repair. 3 Discoidin domain receptor 1 (DDR1) and DDR2 have recently emerged as nonintegrintype receptors for collagen. 4 DDR1 is mainly expressed in epithelial cells, whereas DDR2 is found in mesenchymal cells. 5 DDR1 and DDR2 play potential roles in the regulation of collagen turnover mediated by vascular smooth muscle cells (VSMCs) in obstructive diseases of blood vessel. 6 Both DDRs were found to be highly expressed by SMCs within the fibrous cap. 6 DDR1 has been found to play an important role in mediating intimal thickening after arterial injury 3 ; however, little is known about the function of DDR2 in the vascular system. We have previously demonstrated that stretching of VSMCs in vitro resulted in upregulation of DDR2 expression. 7 In this study we hypothesize that DDR2 plays an important role in vascular injury in vivo. Methods and Results-SMCsRNA interference mediated by small interfering RNA (siRNA) can knock down gene expression at a translational level through interactions with its target messenger RNA 8 and shows great promise for therapeutic applications. 9 Here, we applied RNA interference to study the role of DDR2 in atherosclerosis in vitro and in vivo. Methods siRNA DesignedThe siRNA duplexes targeting the mouse DDR2 mRNA (GenBank accession no. NM_022563) were designed. For the initial screening of the most effective siRNA duplexes, the 21-nucleotide RNAs were synthesized by in vitro transcription (Dharmacon Inc). Further experiments were performed with the most efficient siRNA-duplex. The most efficient siRNA-duplex does have 1 mismatch to the rat sequence NM_031764. The mismatch 1 is located at the 6th base of the duplex, U for mouse and C for rat. No significant similarities to any genes other than DDR2 were found using BLAST against the rat reference sequence database. Vascular Smooth Muscle Cell CulturePrimary cultures of VSMCs were grown by the explant technique from the thoracic aorta of 220-to 260-g male Wistar rats, as Original

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“…p38 was linked to endothelial cell morphological changes (26), ERK is thought to play a role in cell growth (28), and JNK is hypothesized to mediate apoptotic processes (28). In vascular smooth muscle cells, p38 was responsible for mechanotransduction, but JNK was not involved (29). In osteoblasts, both ERK and p38 were involved in transducing mechanical stimuli and up-regulating osteoblast-specific genes (30).…”

Section: Megakaryocytes (Mks)mentioning

confidence: 99%

Megakaryocytic Maturation in Response to Shear Flow Is Mediated by the Activator Protein 1 (AP-1) Transcription Factor via Mitogen-activated Protein Kinase (MAPK) Mechanotransduction

Luff

Papoutsakis

2016

Journal of Biological Chemistry

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Megakaryocytes (MKs) are exposed to shear flow as they migrate from the bone marrow hematopoietic compartment into circulation to release pro/preplatelets into circulating blood. Shear forces promote DNA synthesis, polyploidization, and maturation in MKs, and platelet biogenesis. To investigate mechanisms underlying these MK responses to shear, we carried out transcriptional analysis on immature and mature stem cell-derived MKs exposed to physiological shear. In immature (day (d)9) MKs, shear exposure up-regulated genes related to growth and MK maturation, whereas in mature (d12) MKs, it up-regulated genes involved in apoptosis and intracellular transport.

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Regulation of Discoidin Domain Receptor 2 by Cyclic Mechanical Stretch in Cultured Rat Vascular Smooth Muscle Cells

Cited by 48 publications

References 38 publications

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

RNA Interference for Discoidin Domain Receptor 2 Attenuates Neointimal Formation in Balloon Injured Rat Carotid Artery

Megakaryocytic Maturation in Response to Shear Flow Is Mediated by the Activator Protein 1 (AP-1) Transcription Factor via Mitogen-activated Protein Kinase (MAPK) Mechanotransduction

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