Cerebral angiopathy contributes to cognitive decline and dementia in Alzheimer's disease (AD) through cerebral blood flow (CBF) reductions and dysregulation. We report vascular smooth muscle cells (VSMC) in small pial and intracerebral arteries, which are critical for CBF regulation, express in AD high levels of serum response factor (SRF) and myocardin (MYOCD), two interacting transcription factors that orchestrate a VSMC-differentiated phenotype. Consistent with this finding, AD VSMC overexpressed several SRF-MYOCD-regulated contractile proteins and exhibited a hypercontractile phenotype. MYOCD overexpression in control human cerebral VSMC induced an AD-like hypercontractile phenotype and diminished both endothelial-dependent and -independent relaxation in the mouse aorta ex vivo. In contrast, silencing SRF normalized contractile protein content and reversed a hypercontractile phenotype in AD VSMC. MYOCD in vivo gene transfer to mouse pial arteries increased contractile protein content and diminished CBF responses produced by brain activation in wild-type mice and in two AD models, the Dutch/Iowa/Swedish triple mutant human amyloid beta-peptide (Abeta)-precursor protein (APP)- expressing mice and APPsw(+/-) mice. Silencing Srf had the opposite effect. Expression of SRF did not change in VSMC subjected to Alzheimer's neurotoxin, Abeta. Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of Abeta a pathogenic pathway mediating arterial hypercontractility and CBF dysregulation, which are associated with Alzheimer's dementia.
Objective: Vascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching. Approach and Results: With exposure to free methyl-β-cyclodextrin cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents methyl-β-cyclodextrin cholesterol–induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin, and thapsigargin is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs. Conclusions: Our data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.
The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs25 and p.Glu750) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.
Rationale Mutations in ACTA2, encoding the smooth muscle isoform of α-actin (SM α-actin), cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. Objective We sought to identify the mechanism by which loss of SM α-actin causes aortic disease. Methods and Results Acta2−/− mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2−/− aortas or kidneys. Aortic tissue and explanted smooth muscle cells (SMCs) from Acta2−/− aortas show increased production of reactive oxygen radicals (ROS) and increased basal NF-κB signaling, leading to an increase in the expression of the AngII receptor type I (Agtr1a) and activation of signaling at 100-fold lower levels of AngII in the mutant compared to wild-type cells. Furthermore, disruption of SM α-actin filaments in wildtype SMCs by various mechanisms activates NF-κB signaling and increases expression of Agtr1a. Conclusions These findings reveal that disruption of SM α-actin filaments in SMCs increases ROS levels, activates NF-κB signaling and increases Agtr1a expression, thus potentiating AngII signaling in vascular SMCs without an increase in the exogenous levels of AngII.
Emerging studies have reported the mechanosensitive Piezo1 (piezo type mechanosensitive ion channel component 1) plays essential roles in regulating the vascular tone through mechanistic actions on intracellular calcium homeostasis. However, the specific roles of Piezo1 in pulmonary vessels remain incompletely understood. We aim to investigate whether and how Piezo1 regulates the intracellular calcium homeostasis in human pulmonary arterial smooth muscle cells (PASMCs) under normal and pulmonary arterial hypertension (PAH) conditions. Cultured human PASMCs isolated from both control donors and idiopathic PAH patients were used as cell models. Fura-2 based intracellular calcium imaging was performed to measure the intracellular free calcium concentration ([Ca 2+ ] i ). Results showed that activation of Piezo1 by Yoda1 increases [Ca 2+ ] i by inducing both intracellular calcium release from internal calcium stores through the intracellular (intra-) Piezo1 localized at the subcellular organelles, including endoplasmic reticulum/sarcoplasmic reticulum, mitochondria, and nucleus; as well as extracellular calcium influx through the plasma membrane-localized Piezo1 in a mechanism independent of the store-operated calcium entry. Moreover, the Piezo1-mediated increase of [Ca 2+ ] i is linked to increased contraction and proliferation of PASMCs. Yoda1 induces dose-dependent vasocontraction in endothelium-denuded rat intrapulmonary arteries. Significant upregulation and increased activity of Piezo1 were observed in idiopathic PAH-PASMCs versus donor-PASMCs, contributing to the increased [Ca 2+ ] i and excessive proliferation of idiopathic PAH-PASMCs. In summary, Piezo1 mediates the increase of [Ca 2+ ] i by triggering both intracellular calcium release and extracellular influx. The enhanced Piezo1 expression and activity accounts, at least partially, for the abnormally elevated [Ca 2+ ] i and proliferation in idiopathic PAH-PASMCs.
Alteration in microbiota composition of respiratory tract has been reported in the progression of many chronic lung diseases, yet, the correlation and causal link between respiratory tract microbiota and the disease development of pulmonary hypertension (PH) remain largely unknown. This study aims to define and compare the respiratory microbiota composition in pharyngeal swab samples between patients with PH and reference subjects. A total of 118 patients with PH and 79 reference subjects were recruited, and the pharyngeal swab samples were collected to sequence the 16S ribosomal RNA (16S rRNA) V3-V4 region of respiratory microbiome. The relative abundances in patients with PH were profoundly different from reference subjects. The Ace and Sobs indexes indicated that the microbiota richness of pharynx value is significantly higher; while the community diversity value is markedly lower in patients with PH, comparing to those of the reference subjects. The microbiota on pharynx showed a different profile between the 2 groups by principal component analysis. The linear discriminant analysis effect size also revealed a significantly higher proportion of Streptococcus, Lautropia, and Ralstonia in patients with PH than reference subjects. The linear discriminant analysis effect size output, which represents the microbial gene functions, suggest genes related to bacterial invasion of epithelial cells, bacterial toxins were enhanced, while genes related to energy metabolism, protein digestion and absorption, and cell division pathways were attenuated in patients with PH versus reference subjects. In summary, our study reports the first systematic definition and divergent profile of the upper respiratory tract microbiota between patients with PH and reference subjects.
Background: Genomic duplications involving the smooth muscle myosin heavy chain gene, MYH11, are associated with increased risk for acute aortic dissections. Results: MYH11 overexpression causes increased turnover of contractile proteins through increased autophagy. Conclusion: MYH11 duplications may predispose to aortic disease through increased turnover of contractile proteins and disruption of contractile signaling. Significance: Increased protein turnover may be an important mechanism by which genomic duplications cause human disease.
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