scholarly journals Vascular Smooth Muscle Cell Subpopulations and Neointimal Formation in Mouse Models of Elastin Insufficiency

2021 ◽  
Author(s):  
Chien-Jung Lin ◽  
Bridget Hunkins ◽  
Robyn Roth ◽  
Chieh-Yu Lin ◽  
Jessica E. Wagenseil ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Intimal Hyperplasia ◽  
Ascending Aorta ◽  
Specific Cell ◽  
Neointima Formation ◽  
Neointimal Formation ◽  
Internal Elastic Lamina ◽  
Heart Field ◽  
Secondary Heart Field ◽  
Elastic Lamina

Objective: Using a mouse model of Eln (elastin) insufficiency that spontaneously develops neointima in the ascending aorta, we sought to understand the origin and phenotypic heterogeneity of smooth muscle cells (SMCs) contributing to intimal hyperplasia. We were also interested in exploring how vascular cells adapt to the absence of Eln. Approach and Results: We used single-cell sequencing together with lineage-specific cell labeling to identify neointimal cell populations in a noninjury, genetic model of neointimal formation. Inactivating Eln production in vascular SMCs results in rapid intimal hyperplasia around breaks in the ascending aorta’s internal elastic lamina. Using lineage-specific Cre drivers to both lineage mark and inactivate Eln expression in the secondary heart field and neural crest aortic SMCs, we found that cells with a secondary heart field lineage are significant contributors to neointima formation. We also identified a small population of secondary heart field-derived SMCs underneath and adjacent to the internal elastic lamina. Within the neointima of SMC-Eln knockout mice, 2 unique SMC populations were identified that are transcriptionally different from other SMCs. While these cells had a distinct gene signature, they expressed several genes identified in other studies of neointimal lesions, suggesting that some mechanisms underlying neointima formation in Eln insufficiency are shared with adult vessel injury models. Conclusions: These results highlight the unique developmental origin and transcriptional signature of cells contributing to neointima in the ascending aorta. Our findings also show that the absence of Eln, or changes in elastic fiber integrity, influences the SMC biological niche in ways that lead to altered cell phenotypes.

scholarly journals An in silico study on the role of smooth muscle cell migration in neointimal formation after coronary stenting

2015 ◽  
Vol 12 (108) ◽  
pp. 20150358 ◽  
Author(s):  
Hannan Tahir ◽  
Ioana Niculescu ◽  
Carles Bona-Casas ◽  
Roeland M. H. Merks ◽  
Alfons G. Hoekstra
Keyword(s):  
Smooth Muscle ◽  
Coronary Stenting ◽  
Cellular Potts Model ◽  
Neointimal Formation ◽  
Internal Elastic Lamina ◽  
Stent Deployment ◽  
Early Migration ◽  
Elastic Lamina

Excessive migration and proliferation of smooth muscle cells (SMCs) has been observed as a major factor contributing to the development of in-stent restenosis after coronary stenting. Building upon the results from in vivo experiments, we formulated a hypothesis that the speed of the initial tissue re-growth response is determined by the early migration of SMCs from the injured intima. To test this hypothesis, a cellular Potts model of the stented artery is developed where stent struts were deployed at different depths into the tissue. An extreme scenario with a ruptured internal elastic lamina was also considered to study the role of severe injury in tissue re-growth. Based on the outcomes, we hypothesize that a deeper stent deployment results in on average larger fenestrae in the elastic lamina, allowing easier migration of SMCs into the lumen. The data also suggest that growth of the neointimal lesions owing to SMC proliferation is strongly dependent on the initial number of migrated cells, which form an initial condition for the later phase of the vascular repair. This mechanism could explain the in vivo observation that the initial rate of neointima formation and injury score are strongly correlated.

An Arteriovenous Malformation Model for Stereotactic Radiosurgery Research

Neurosurgery ◽  
2007 ◽  
Vol 61 (1) ◽  
pp. 152-159 ◽  
Author(s):  
Reza Jahan ◽  
Timothy D. Solberg ◽  
Daniel Lee ◽  
Paul Medin ◽  
Satoshi Tateshima ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Arteriovenous Malformation ◽  
Smooth Muscle Cells ◽  
Stereotactic Radiosurgery ◽  
Intimal Hyperplasia ◽  
Morphological Changes ◽  
Muscle Cells ◽  
Collagen Type Iv ◽  
Internal Elastic Lamina ◽  
Type Iv

Abstract OBJECTIVE To introduce the utilization of a swine arteriovenous malformation (AVM) model for stereotactic radiosurgery research and to describe the morphological changes in the vessels after radiation. METHODS The model was created in six animals by creation of a right-sided carotid-jugular fistula. Pre- and postsurgical hemodynamic evaluation was performed. The left rete was radiated in four animals; two animals were not radiated. All animals were sacrificed 4 months after surgery, and the bilateral retia were obtained at autopsy. RESULTS There were no procedure-related complications. A pressure gradient of 20 mmHg across the nidus was obtained after surgery. The peak velocity in the arterial feeder increased from 18.5 to 83 cm/s. Microscopic examination of the control animals showed intimal hyperplasia and disrupted internal elastic lamina, similar to human AVMs. The radiated retia showed more prominent intimal hyperplasia. This was confirmed by histometric studies showing greater luminal occlusion in radiated specimens. Adventitial fibrosis was prominent in the radiated retia and was absent in the control animals. Immunohistochemical studies showed proliferating smooth muscle cells in the intima. The adventitial fibrosis consisted of smooth muscle cells surrounded by collagen Type IV extracellular matrix. CONCLUSION The nidus component and high-flow vasculopathy make this an attractive model for stereotactic radiosurgery research. Histology of the radiated models is similar to those described in radiated human AVMs. Further studies of the model are warranted to gain a better understanding of the cellular and molecular events in AVM vessels after stereotactic radiosurgery.

Smooth muscle pattern is more reliable than the presence or absence of an internal elastic lamina in distinguishing an artery from a vein

2006 ◽  
Vol 33 (3) ◽  
pp. 216-219 ◽  
Author(s):  
Scott R. Dalton ◽  
Eric P. Fillman ◽  
Tammie Ferringer ◽  
William Tyler ◽  
Dirk M. Elston
Keyword(s):  
Smooth Muscle ◽  
Internal Elastic Lamina ◽  
Elastic Lamina

Exogenous Perioxidase Localization in Irradiated Arteries

1972 ◽  
Vol 30 ◽  
pp. 8-9
Author(s):  
James C. Hampton ◽  
Benjamin Rosario ◽  
Roy R. Adee
Keyword(s):  
Smooth Muscle ◽  
Horseradish Peroxidase ◽  
Mesenteric Artery ◽  
Type Ii ◽  
Internal Elastic Lamina ◽  
Small Branch ◽  
X Irradiation ◽  
The Media ◽  
Intrasplenic Injection ◽  
Elastic Lamina

Mice were exposed to 1500 R X-irradiation and sacrificed on days 1,2,3,3.5 and 4 days postexposure. Two to 3 min before sacrifice each mouse received 5 mg horseradish peroxidase (Sigma type II) in 0.5 ml saline by intrasplenic injection. Tissues were fixed in glutaraldehyde-formaldehyde and incubated according to the method of Karnovsky for histochemical localization of horseradish peroxidase (HRP). Unirradiated tissues and irradiated but unincubated tissues were used as controls.Figure 1 shows only moderate staining of the internal elastic lamina (IEL) in a small branch of the mesenteric artery at 3 days postirradiation. No evidence of deposits of HRP reaction product was observed in either the endothelium or smooth muscle of the media.

Interstitial flow through the internal elastic lamina affects shear stress on arterial smooth muscle cells

2000 ◽  
Vol 278 (5) ◽  
pp. H1589-H1597 ◽  
Author(s):  
Shigeru Tada ◽  
John M. Tarbell
Keyword(s):  
Shear Stress ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Shear Stresses ◽  
Interstitial Flow ◽  
Internal Elastic Lamina ◽  
Tunica Media ◽  
Flow Through ◽  
Elastic Lamina

Interstitial flow through the tunica media of an artery wall in the presence of the internal elastic lamina (IEL), which separates it from the subendothelial intima, has been studied numerically. A two-dimensional analysis applying the Brinkman model as the governing equation for the porous media flow field was performed. In the numerical simulation, the IEL was modeled as an impermeable barrier to water flux, except for the fenestral pores, which were uniformly distributed over the IEL. The tunica media was modeled as a heterogeneous medium composed of a periodic array of cylindrical smooth muscle cells (SMCs) embedded in a fiber matrix simulating the interstitial proteoglycan and collagen fibers. A series of calculations was conducted by varying the physical parameters describing the problem: the area fraction of the fenestral pore (0.001–0.036), the diameter of the fenestral pore (0.4–4.0 μm), and the distance between the IEL and the nearest SMC (0.2–0.8 μm). The results indicate that the value of the average shear stress around the circumference of the SMC in the immediate vicinity of the fenestral pore could be as much as 100 times greater than that around an SMC in the fully developed interstitial flow region away from the IEL. These high shear stresses can affect SMC physiological function.

scholarly journals Mature Vascular Smooth Muscle Cells, but Not Endothelial Cells, Serve as the Major Cellular Source of Intimal Hyperplasia in Vein Grafts

2020 ◽  
Vol 40 (8) ◽  
pp. 1870-1890 ◽  
Author(s):  
Weiwei Wu ◽  
Chunyan Wang ◽  
Huimei Zang ◽  
Lei Qi ◽  
Mohamad Azhar ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Intimal Hyperplasia ◽  
Neointima Formation ◽  
Mesenchymal Transition ◽  
Cellular Source ◽  
Endothelial To Mesenchymal Transition

Objective: Neointima formation is a primary cause of intermediate to late vein graft (VG) failure. However, the precise source of neointima cells in VGs remains unclear. Approach and Results: Herein we clarify the relative contributions of mature vascular smooth muscle cells (SMCs) and endothelial cells (ECs) to neointima formation in a mouse model of VG remodeling via the genetic-inducible fate mapping approaches. Regardless of the magnitude of neointima formation, the recipient arterial and the donor venous SMCs contributed ≈55% of the neointima cells at the anastomotic regions, whereas only donor venous SMCs donated ≈68% of the neointima cells at the middle bodies. A small portion of the SMC-derived cells became non-SMC cells, most likely vascular stem cells, and constituted 2% to 11% of the cells in each major layer of VGs. In addition, the recipient arterial ECs were the major cellular source of re-endothelialization but did not contribute to neointima formation. The donor venous ECs donated ≈17% neointima cells in the VGs with mild neointima formation and conditional media from ECs after endothelial-to-mesenchymal transition suppressed vascular SMC dedifferentiation. Conclusions: The recipient arterial and donor venous mature SMCs dominate but contribute distinctly to intimal hyperplasia at the anastomosis and the middle body regions of VGs. The recipient arterial ECs are the major cellular source of re-endothelialization but do not donate neointima formation in VGs. Only the donor venous ECs undergo endothelial-to-mesenchymal transition. Endothelial-to-mesenchymal transition is marginal for generating neointima cells but is likely required for controlling the quality of VG remodeling.

scholarly journals Functional Role of Second Heart Field-derived Smooth Muscle Cells in Thoracic Aortopathies in Mice

2020 ◽  
Author(s):  
Hisashi Sawada ◽  
Hideyuki Higashi ◽  
Chen Zhang ◽  
Yanming Li ◽  
Yuriko Katsumata ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Neural Crest ◽  
Single Cell ◽  
Proteomic Analysis ◽  
Ascending Aorta ◽  
Second Heart Field ◽  
Heart Field

AbstractBackgroundThe ascending aorta is a common location for thoracic aortopathies. Pathology predominates in the aortic media with disease severity being most apparent in outer laminar layers. In the ascending aorta, smooth muscle cells (SMCs) are derived from two embryonic origins: cardiac neural crest and second heart field (SHF). SMCs of these origins have distinct distributions, and the localization of SHF coincides with the regional specificity in some forms of thoracic aortopathies. However, the role of SHF-derived SMCs in maintaining the structural and functional integrity of the ascending aorta remains unclear.MethodsMass spectrometry assisted proteomic and single cell transcriptomic analyses were performed in mouse aortas to discriminate molecular features of SHF-derived SMCs in maintaining the aortic homeostasis. Genetic deletion of low-density lipoprotein receptor-related protein 1 (Lrp1) or transforming growth factor-β receptor 2 (Tgfbr2) in SHF-derived SMCs was conducted to examine impact of SHF-derived SMCs on the development of thoracic aortopathies.ResultsProteomic analysis did not detect differences in protein profiles between ascending (disease prone) and descending (disease resistant) thoracic aortas in saline-infused mice. However, angiotensin II infusion altered these profiles in a region-specific manner. Angiotensin II evoked differential expression of multiple LRP1 ligands. Histological analysis demonstrated that angiotensin II-induced medial disruptions were detected mainly in outer laminar layers derived from the SHF. Single cell RNA sequencing using normal mouse aortas revealed lower abundance of elastin mRNA in SHF-derived SMCs compared to SMCs from the cardiac neural crest. In addition, Lrp1 and Tgfbr2 mRNA were abundant in SHF-derived SMCs. To examine biological effects of SHF-derived cells, Lrp1 or Tgfbr2 was deleted in SHF-derived cells in mice. SHF-specific Lrp1 deletion augmented angiotensin II-induced aortic aneurysm and rupture in the ascending region. Proteomic analysis discerned regulation of protein abundances related to TGF-β signaling pathways by Lrp1 deletion in SHF-derived cells. Deletion of Tgfbr2, a key regulator of TGF-β signaling, in SHF-derived cells led to embryonic lethality at E12.5 with dilatation of the outflow tract and retroperitoneal hemorrhage in mice.ConclusionThese results demonstrate that SMCs derived from the SHF play a critical role in the integrity of the ascending aortic wall.

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