Abstract 128: LRP1 Deletion in Smooth Muscle Cells of the Outer Aortic Media Promotes Angiotensin II-induced Thoracic Aortic Aneurysm

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Hisashi Sawada ◽  
Debra L Rateri ◽  
Mark W Majesky ◽  
Alan Daugherty
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Rupture ◽  
Muscle Cells ◽  
Lineage Tracing ◽  
Second Heart Field ◽  
Heart Field

Objective: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional protein that is linked to several vascular pathologies. LRP1 deletion in smooth muscle cells (SMCs) accelerates angiotensin II (AngII)-induced thoracic aortic aneurysm (TAA). In association with TAA formation, there is medial thickening that is characterized by a transmural gradient in which pathology progressively increases from lumen to adventitial aspect. We hypothesized that deletion of LRP1 in the outer medial layers of the proximal thoracic aorta has a pivotal role in the pathogenesis of TAA. The aim of this study was to determine whether LRP1 deletion in the outer media accelerates AngII-induced TAA formation. Methods and Results: SMCs in the outer media of the ascending aorta are derived from the second heart field, as demonstrated by lineage tracing studies using Cre under the control of Mef2c. Therefore, we used Mef2c-driven Cre to delete LRP1 in SMCs of the outer medial layers. Female LRP1 flox/flox mice were bred to male Mef2c-Cre1/0 mice to generate study mice. We first confirmed LRP1 deletion in Cre1/0 mice by both immunostaining and Western blot. LRP1 was expressed ubiquitously across smooth muscle cells of all aortic medial layers in Cre 0/0 mice. In mice expressing Mef2c-Cre, aortic LRP1 protein was detected only in SMCs of the inner laminar medial layers. Western blotting demonstrated LRP1 protein abundance in Cre expressing mice was reduced by 43%. Saline or AngII (1,000 ng/kg/min) was infused by subcutaneous osmotic pumps for 28 days into 12 - 14 week-old male Cre0/0 and 1/0 mice. As expected, systolic blood pressure increased similarly in both AngII-infused Cre 0/0 and 1/0 mice compared to saline-infused mice. Aortic rupture occurred within 3 to 10 days after AngII infusion in 17% of AngII-infused Cre 0/0 mice, while LRP1 deletion in Cre 1/0 mice increased aortic rupture to 27%. Aortic diameter in the survivors was significantly increased in Cre1/0 mice compared to Cre0/0 mice. Histologically, elastin fragmentation was detected in the aorta of AngII-infused Cre 0/0 mice and greater in Cre1/0 mice. Conclusion: LRP1 in second heart field-derived SMCs of the outer media may play a critical role in the pathogenesis of TAA.

scholarly journals Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms

2021 ◽  
Author(s):  
Haocheng Lu ◽  
Wa Du ◽  
Lu Ren ◽  
Milton H. Hamblin ◽  
Richard C. Becker ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Thoracic Aortic Aneurysm ◽  
Muscle Cells ◽  
Abdominal Aortic ◽  
Aneurysm Development

Abstract Aortic aneurysm, including thoracic aortic aneurysm and abdominal aortic aneurysm, is the second most prevalent aortic disease following atherosclerosis, representing the ninth‐leading cause of death globally. Open surgery and endovascular procedures are the major treatments for aortic aneurysm. Typically, thoracic aortic aneurysm has a more robust genetic background than abdominal aortic aneurysm. Abdominal aortic aneurysm shares many features with thoracic aortic aneurysm, including loss of vascular smooth muscle cells (VSMCs), extracellular matrix degradation and inflammation. Although there are limitations to perfectly recapitulating all features of human aortic aneurysm, experimental models provide valuable tools to understand the molecular mechanisms and test novel therapies before human clinical trials. Among the cell types involved in aortic aneurysm development, VSMC dysfunction correlates with loss of aortic wall structural integrity. Here, we discuss the role of VSMCs in aortic aneurysm development. The loss of VSMCs, VSMC phenotypic switching, secretion of inflammatory cytokines, increased matrix metalloproteinase activity, elevated reactive oxygen species, defective autophagy, and increased senescence contribute to aortic aneurysm development. Further studies on aortic aneurysm pathogenesis and elucidation of the underlying signaling pathways are necessary to identify more novel targets for treating this prevalent and clinical impactful disease.

microRNA expression profile in Smooth Muscle Cells isolated from thoracic aortic aneurysm samples

2019 ◽  
Vol 64 (2) ◽  
pp. 331-337 ◽  
Author(s):  
Anna Kasprzyk-Pawelec ◽  
Anna Wojciechowska ◽  
Mateusz Kuc ◽  
Jakub Zielinski ◽  
Adam Parulski ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Expression Profile ◽  
Thoracic Aortic Aneurysm ◽  
Muscle Cells ◽  
Microrna Expression ◽  
Microrna Expression Profile

Extracellular matrix metalloproteinase inducer (EMMPRIN) is present in smooth muscle cells of human aneurysmal aorta and is induced by angiotensin II in vitro

2009 ◽  
Vol 116 (11) ◽  
pp. 819-826 ◽  
Author(s):  
Xiao-feng Chen ◽  
Jian-an Wang ◽  
Jun Hou ◽  
Chun Gui ◽  
Li-jiang Tang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Matrix Metalloproteinase ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Extracellular Matrix Metalloproteinase Inducer

The aim of the present study was to determine whether EMMPRIN (extracellular matrix metalloproteinase inducer) is present and is up-regulated in human aneurysmal aortas, and to assess a possible association with AngII (angiotensin II)-induced aneurysm formation. The presence of EMMPRIN was assessed in 41 surgical specimens from patients with a TAA (thoracic aortic aneurysm) (Type A aortic dissection, n=12; Type B aortic dissection, n=7; and TAA without dissection, n=7) or an AAA (abdominal aortic aneurysm, n=15) by immunohistochemistry. EMMPRIN expression in aortic aneurysm tissues was compared with 12 aortas obtained during autopsy (free of any vascular diseases), and scored for both staining intensity and the percentage of vascular cells stained. EMMPRIN protein levels in cultured human aortic SMCs (smooth muscle cells) following stimulation of AngII were analysed by Western blotting. Significant EMMPRIN immunoreactivity was detected in aortic aneurysm lesions from patients with TAAs and AAAs. In the aneurysmal wall, α-actin-positive SMCs were the main source of EMMPRIN. The frequency of EMMPRIN overexpression was significantly higher (P=0.026) in TAAs with dissection (68.4%) than TAAs without dissection (14.3%). AngII stimulation up-regulated the expression of EMMPIRN in cultured human aortic SMCs, which was suppressed by the addition of the AT1R (AngII type 1 receptor) antagonist losartan. In conclusion, the present study is the first to report the expression of EMMPRIN in aortic aneurysmal diseases, and we speculate that EMMPRIN may be important in the pathogenesis of these diseases. Whether these abnormalities are potential therapeutic targets deserve further investigation.

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.

Abstract 397: Analysis of Cell Phenotype in Relation to TGFβ Treatment of Aortic Smooth Muscle Cells and Myofibroblasts Isolated from Aortas and Valves of Thoracic Aortic Aneurysm Patients with a Tricuspid or a Bicuspid Valve

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Valentina Paloschi ◽  
Lasse Folkersen ◽  
Sanela Kurtovic ◽  
Dick Wagsater ◽  
Anders Franco Cereceda ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Thoracic Aortic Aneurysm ◽  
Muscle Cells ◽  
Cell Types ◽  
Cell Phenotype ◽  
Matrix Remodeling ◽  
Exon Arrays

Background Thoracic aortic aneurysm (TAA) is a pathological widening of the aorta, due to degeneration of extracellular matrix (ECM) and loss of smooth muscle cells (SMCs). Bicuspid aortic valve (BAV) is a congenital disorder present in 1-2 % of the population which makes TAA associated with BAV a common complication. Previously we showed that aortas isolated from BAV and normal tricuspid aortic valve (TAV) patients are different both at gene and protein levels. Particularly, differences in the TGFβ pathway seem to be crucial players in aneurysm development, affecting matrix remodeling and wound healing. Since SMCs and myofibroblasts are the critical cells responsible for these activities, we evaluated different properties of the cells focusing on fibronectin (FN) and its spliced versions, a target gene of TGFβ. Interestingly, extra domain A of FN (EDA) was previously described for its roles in vascular morphogenesis, as well as in processes like migration and proliferation. Methods and results Biopsies from the thoracic aorta and Aortic valves were collected during Elective Aortic Valve Replacement Surgery. mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=46) and BAV (n=77). Expression of EDA was found increased only in dilated aortas from TAV patients but not in BAV patients. Primary SMCs were isolated with the explant outgrowth technique from aortas of BAV and TAV patients (n=15). Myofibroblasts were isolated by collagenase digestion from BAV and TAV valves (n=30). Cells were cultured and treated with TGFβ at a concentration of 20 ng/ml for 6h. TGFβ treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in SMCs from TAV patients but not in cells derived from BAV patients. We have not observed clear differences in SMC proliferation and migration. Myofibrolasts analysis is ongoing. Conclusions So far, our results suggest that despite a decreased EDA-fibronectin expression in BAV cells, the phenotype of SMCs isolated from BAV and TAV patients in culture does not differ. However, impaired TGFβ signaling that may result in the increased susceptibility of BAV patients to develop TAA could be due to effects on other cell types.

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