Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats

2003 ◽  
Vol 284 (1) ◽  
pp. L148-L159 ◽  
Author(s):  
Lyn M. Moir ◽  
Sum-Yee Leung ◽  
Paul R. Eynott ◽  
Clare G. McVicker ◽  
Jeremy P. T. Ward ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Structural Changes ◽  
Ex Vivo ◽  
Contractile Protein ◽  
Brown Norway ◽  
Phenotypic Modulation ◽  
Allergen Inhalation ◽  
Kinase Expression ◽  
Norway Rats

Repeated ovalbumin (OA) or saline exposure of sensitized Brown Norway rats was examined on agonist reactivity, airway smooth muscle (ASM) content, and contractile protein expression in small bronchioles at 24 h, 7 days, and 35 days after challenge. OA increased ASM content ( P < 0.05 vs. saline) at 24 h, which resolved by 7 days. Maximum developed tension (Tmax) to carbachol, KCl, and 4-β-phorbol 12,13-dibutyrate was increased ( P < 0.05) by OA in bronchioles at 24 h but was abrogated after correction for ASM. Differences in Tmaxwere not present at 7 days. In contrast, at 35 days, Tmaxwas increased ( P < 0.05) after correction for ASM. Smooth muscle (sm)-α-actin, sm-myosin heavy chain (MHC) isoform 1, calponin, smoothelin-A, and sm-myosin light chain kinase expression were reduced ( P < 0.05) by OA at 24 h in bronchioles but not in trachealis. Consistent with contraction findings, no difference in expression of these proteins was detected at 7 days. At 35 days, however, with the exception of sm-α-actin, their abundance was again reduced ( P < 0.05) by OA. Nonmuscle MHC and β-actin were unchanged throughout by OA. These findings indicate persistent changes in contractile protein content, consistent with ASM phenotypic modulation in vivo, which occur in response to repeated OA inhalation. Thus, OA exposure induces structural changes in bronchiole ASM content and in agonist responsiveness ex vivo that resemble remodeling in asthma.

scholarly journals Surfactant Protein A, a Novel Regulator for Smooth Muscle Phenotypic Modulation and Vascular Remodeling

2020 ◽  
Author(s):  
Ran Ran ◽  
Dunpeng Cai ◽  
Skylar D. King ◽  
Xingyi Que ◽  
Jonathan M. Bath ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Protein Expression ◽  
Vascular Remodeling ◽  
Protein A ◽  
Surfactant Protein ◽  
Surfactant Protein A ◽  
Contractile Protein ◽  
Phenotypic Modulation

Objective: The objective of this study is to determine the role of SPA (surfactant protein A) in vascular smooth muscle cell (SMC) phenotypic modulation and vascular remodeling. Approach and Results: PDGF-BB (Platelet-derived growth factor-BB) and serum induced SPA expression while downregulating SMC marker gene expression in SMCs. SPA deficiency increased the contractile protein expression. Mechanistically, SPA deficiency enhanced the expression of myocardin and TGF (transforming growth factor)-β, the key regulators for contractile SMC phenotype. In vivo, SPA was induced in medial and neointimal SMCs following mechanical injury in both rat and mouse carotid arteries. SPA knockout in mice dramatically attenuated the wire injury-induced intimal hyperplasia while restoring SMC contractile protein expression in medial SMCs. These data indicate that SPA plays an important role in SMC phenotype modulation and vascular remodeling in vivo. Conclusions: SPA is a novel protein factor modulating SMC phenotype. Blocking the abnormal elevation of SPA may be a potential strategy to inhibit the development of proliferative vascular diseases.

The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma

2009 ◽  
Vol 297 (4) ◽  
pp. L698-L705 ◽  
Author(s):  
Isabelle Labonté ◽  
Muhannad Hassan ◽  
Paul-André Risse ◽  
Kimitake Tsuchiya ◽  
Michel Laviolette ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Ex Vivo ◽  
Mrna Level ◽  
Allergen Challenge ◽  
Airway Responsiveness ◽  
Brown Norway ◽  
Contractile Phenotype ◽  
The Relationship

The effects of remodeling of airway smooth muscle (SM) by hyperplasia on airway SM contractility in vivo are poorly explored. The aim of this study was to investigate the relationship between allergen-induced airway SM hyperplasia and its contractile phenotype. Brown Norway rats were sensitized with ovalbumin (OVA) or saline on day 0 and then either OVA-challenged once on day 14 and killed 24 h later or OVA-challenged 3 times (on days 14, 19, and 24) and killed 2 or 7 days later. Changes in SM mass, expression of total myosin, SM myosin heavy chain fast isoform (SM-B) and myosin light chain kinase (MLCK), tracheal contractions ex vivo, and airway responsiveness to methacholine (MCh) in vivo were assessed. One day after a single OVA challenge, the number of SM cells positive for PCNA was greater than for control animals, whereas the SM mass, contractile phenotype, and tracheal contractility were unchanged. Two days after three challenges, SM mass and PCNA immunoreactive cells were increased (3- and 10-fold, respectively; P < 0.05), but airway responsiveness to MCh was unaffected. Lower expression in total myosin, SM-B, and MLCK was observed at the mRNA level ( P < 0.05), and total myosin and MLCK expression were lower at the protein level ( P < 0.05) after normalization for SM mass. Normalized tracheal SM force generation was also significantly lower 2 days after repeated challenges ( P < 0.05). Seven days after repeated challenges, features of remodeling were restored toward control levels. Allergen-induced hyperplasia of SM cells was associated with a loss of contractile phenotype, which was offset by the increase in mass.

Regulation of SM22α expression by arginine vasopressin and PDGF-BB in vascular smooth muscle cells

2003 ◽  
Vol 285 (4) ◽  
pp. H1444-H1452 ◽  
Author(s):  
Nihal Kaplan-Albuquerque ◽  
Chrystelle Garat ◽  
Vicki Van Putten ◽  
Raphael A. Nemenoff
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Arginine Vasopressin ◽  
Promoter Activity ◽  
Serum Response Factor ◽  
Phenotypic Modulation ◽  
Carg Box ◽  
Pdgf Signaling

Vascular smooth muscle (SM) cells (VSMC) undergo phenotypic modulation in vivo and in vitro. This process involves coordinated changes in expression of multiple SM-specific genes. In cultured VSMC, arginine vasopressin (AVP) increases and PDGF decreases expression of SM α-actin (SMA), the earliest marker of SM cells (SMC). However, it is unknown whether these agents regulate other SM genes in a similar fashion. SM22α appears secondary to SMA during development and is also a marker for SMC. This study examined the regulation of SM22α expression by AVP and PDGF in cultured VSMC. Levels of SM22α mRNA and protein were increased by AVP and suppressed by PDGF. Consistent with these changes, AVP increased SM22α promoter activity, whereas PDGF inhibited basal promoter activity and blocked AVP-induced increase. Activation of both JNK and p38 MAPK pathways was necessary for AVP-mediated induction of SM22α promoter. Expression of constitutively active Ras produced similar suppressions on SM22α promoter activity as PDGF. Signaling relayed from PDGF/Ras activation involved Raf, or a protein that competes for this site, Ral-GDS, and phosphatidylinositol 3-kinase activation. Truncational analysis showed that the proximal location of three CArG boxes in the promoter was sufficient for AVP stimulation. Mutations in this CArG box reduced basal and AVP-stimulated promoter activity without effecting PDGF suppression. Overexpression of serum response factor enhanced basal and AVP-stimulated promoter activity but had no effect on PDGF-BB-induced suppression. These data indicate that AVP and PDGF initiate specific signaling pathways that control expression of multiple SM genes leading to phenotypic modulation.

scholarly journals Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm

2020 ◽  
Vol 21 (17) ◽  
pp. 6334
Author(s):  
Rijan Gurung ◽  
Andrew Mark Choong ◽  
Chin Cheng Woo ◽  
Roger Foo ◽  
Vitaly Sorokin
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Aortic Wall ◽  
Epigenetic Mechanisms ◽  
Phenotypic Modulation ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in AAA formation and reflects the importance of SMCs plasticity in AAA formation. Although evidence from the wide variety of mouse models is convincing, how this knowledge is applied to human biology needs to be addressed urgently leveraging modern in vitro and in vivo experimental technology.

scholarly journals Repeated allergen inhalations induce DNA synthesis in airway smooth muscle and epithelial cells in vivo

1998 ◽  
Vol 274 (3) ◽  
pp. L417-L424 ◽  
Author(s):  
Reynold A. Panettieri ◽  
Richard K. Murray ◽  
Andrew J. Eszterhas ◽  
Gulsevil Bilgen ◽  
James G. Martin
Keyword(s):  
Smooth Muscle ◽  
Epithelial Cells ◽  
Basement Membrane ◽  
Dna Synthesis ◽  
Airway Smooth Muscle ◽  
Allergen Challenge ◽  
Brown Norway ◽  
Small Airways ◽  
Airway Epithelial

Airway smooth muscle (ASM) mass appears to be increased in the bronchi of patients with chronic severe asthma. Although the precise mechanisms that induce these changes are unknown, increases in ASM mass are caused, in part, by ASM cell proliferation. After allergen challenge in rats, it has been possible to demonstrate an increase in ASM mass by morphometric techniques. To examine whether hyperplasia is involved in ASM cell growth in vivo, we investigated whether repeated allergen challenges in sensitized Brown Norway rats stimulated DNA synthesis in airway epithelial and ASM cells. Animals that were actively sensitized to ovalbumin (OA) received either three aerosolized OA or saline challenges at 5-day intervals. DNA synthesis was measured by indirect immunohistochemical techniques with an anti-bromodeoxyuridine (BrdU) antibody. OA inhalations increased ASM mass as determined by morphometry and also induced DNA synthesis in both airway epithelial and ASM cells in the airways of sensitized animals compared with saline-challenged control animals. ASM mass was increased in large- and medium-sized airways but not in small airways. However, the number of BrdU-positive ASM cells normalized to basement membrane length was also greater in the large- and medium-sized airways compared with that in the small airways. When the number of BrdU-positive epithelial cells was normalized to basement membrane length, there was no difference among airway sizes and the number of BrdU-positive epithelial cells. These data suggest that DNA synthesis is induced in both airway epithelial and ASM cells after inhalational antigen challenge.

scholarly journals Sustained scleral stiffening in rats after a single genipin treatment

2019 ◽  
Vol 16 (159) ◽  
pp. 20190427 ◽  
Author(s):  
Bailey G. Hannon ◽  
Stephen A. Schwaner ◽  
Elizabeth M. Boazak ◽  
Brandon G. Gerberich ◽  
Erin J. Winger ◽  
...  
Keyword(s):  
Digital Image Correlation ◽  
Digital Image ◽  
Image Correlation ◽  
Brown Norway ◽  
Post Injection ◽  
Functional Studies ◽  
Multiple Treatments ◽  
Lagrange Strain ◽  
Norway Rats

Scleral stiffening has been proposed as a therapy for glaucoma and myopia. Previous in vivo studies have evaluated the efficacy of scleral stiffening after multiple treatments with a natural collagen crosslinker, genipin. However, multiple injections limit clinical translatability. Here, we examined whether scleral stiffening was maintained after four weeks following a single genipin treatment. Eyes from brown Norway rats were treated in vivo with a single 15 mM genipin retrobulbar injection, sham retrobulbar injection, or were left naive. Eyes were enucleated either 1 day or four weeks post-injection and underwent whole globe inflation testing. We assessed first principal Lagrange strain of the posterior sclera using digital image correlation as a proxy for scleral stiffness. Four weeks post-injection, genipin treatment resulted in a 58% reduction in scleral strain as compared to controls ( p = 0.005). We conclude that a single in vivo injection of genipin effectively stiffened rat sclera for at least four weeks which motivates further functional studies and possible clinical translation of genipin-induced scleral stiffening.

scholarly journals Lineage Tracing Reveals the Dynamic Contribution of Pericytes to the Blood Vessel Remodeling in Pulmonary Hypertension

2020 ◽  
Vol 40 (3) ◽  
pp. 766-782 ◽  
Author(s):  
Jennifer Bordenave ◽  
Ly Tu ◽  
Nihel Berrebeh ◽  
Raphaël Thuillet ◽  
Amélie Cumont ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Structural Changes ◽  
Chronic Hypoxia ◽  
Transforming Growth Factor ◽  
Primary Cultures ◽  
Lineage Tracing ◽  
In Vivo Model ◽  
Dependent Manner

Objective: Excessive accumulation of resident cells within the pulmonary vascular wall represents the hallmark feature of the remodeling occurring in pulmonary arterial hypertension (PAH). Furthermore, we have previously demonstrated that pulmonary arterioles are excessively covered by pericytes in PAH, but this process is not fully understood. The aim of our study was to investigate the dynamic contribution of pericytes in PAH vascular remodeling. Approach and Results: In this study, we performed in situ, in vivo, and in vitro experiments. We isolated primary cultures of human pericytes from controls and PAH lung specimens then performed functional studies (cell migration, proliferation, and differentiation). In addition, to follow up pericyte number and fate, a genetic fate-mapping approach was used with an NG2CreER;mT/mG transgenic mice in a model of pulmonary arteriole muscularization occurring during chronic hypoxia. We identified phenotypic and functional abnormalities of PAH pericytes in vitro, as they overexpress CXCR (C-X-C motif chemokine receptor)-7 and TGF (transforming growth factor)-βRII and, thereby, display a higher capacity to migrate, proliferate, and differentiate into smooth muscle-like cells than controls. In an in vivo model of chronic hypoxia, we found an early increase in pericyte number in a CXCL (C-X-C motif chemokine ligand)-12-dependent manner whereas later, from day 7, activation of the canonical TGF-β signaling pathway induces pericytes to differentiate into smooth muscle-like cells. Conclusions: Our findings reveal a pivotal role of pulmonary pericytes in PAH and identify CXCR-7 and TGF-βRII as 2 intrinsic abnormalities in these resident progenitor vascular cells that foster the onset and maintenance of PAH structural changes in blood lung vessels.

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