Biology subjects

Moorleghen, J. J.

Publications and source records attributed to Moorleghen, J. J..

14 recordsLinked to original sources

bioRxiv2026

Angiotensin II Promotes Mitral Valve and Left Atrial Pathology in Fibrillin-1C1041G/+ Mice

Background: Activation of the renin-angiotensin system (RAS) contributes to aortic diseases caused by fibrillin-1 haploinsufficiency (Fbn1C1041G/+). However, whether RAS activation influences mitral valve disease associated with FBN1 variants remains undefined. This study determined whether inhibition or augmentation of the RAS affects mitral valve pathology in Fbn1C1041G/+ mice. Methods: Angiotensinogen (AGT) antisense oligonucleotides (ASOs) were administered for 12 weeks to inhibit the RAS in male and female Fbn1C1041G/+ mice. To augment the RAS, mice were infused with angiotensin II (AngII; 1,000 ng/kg/min) for 28 days. Mitral valve and heart function were monitored by ultrasound. At termination, hearts were dissected free and tissue sectioned to assess mitral valve leaflet thickness and pathology. Results: Mitral valve leaflet thickness was significantly increased in Fbn1C1041G/+ mice compared to Fbn1+/+ littermates of both sexes. ASO-mediated AGT inhibition did not alter this phenotype despite markedly reduced plasma AGT concentrations. AngII infusion increased mitral valve leaflet thickness in Fbn1C1041G/+ mice with increased proteoglycan and collagen content, while exerting minimal effects in Fbn1+/+ mice. Twenty-five percent of AngII-infused Fbn1C1041G/+ mice died of non-vascular causes. Ultrasound showed mitral valve dysfunction in AngII-infused Fbn1C1041G/+ mice. Grossly expanded left atria were common in AngII-infused Fbn1C1041G/+ mice. These markedly enlarged left atria contained increased fibrosis, macrophage accumulation, and platelet-rich masses. Conclusions: Mitral valves of Fbn1C1041G/+ mice did not respond to AGT inhibition but were markedly more susceptible to AngII infusion, with greater increases in thickness and compositional changes than mitral valves of Fbn1+/+ mice. In addition, AngII promoted mitral valve dysfunction that were associated with pronounced left atrial pathology.

pharmacology and toxicology↗

bioRxiv2025

Angiotensin II Induces Abdominal Aortic Branch Aneurysms in Fibrillin-1C1041G/+ Mice

BackgroundMice harboring a missense variant (C1041G) of fibrillin-1 (Fbn1) have been used extensively for aortopathy research, but do not mimic all facets of the human disease. The role of increased angiotensin II (AngII) or blood pressure in determining the arterial phenotype of these mice remains incompletely defined. The purpose of this study was to determine whether AngII, either directly or indirectly through increased blood pressure, promotes pathology in the proximal thoracic aorta and beyond. MethodsFbn1+/+ and Fbn1C1041G/+ littermates were infused with either AngII or norepinephrine (NE) via subcutaneously implanted osmotic pumps. Micro computed tomography (microCT) was used to visualize vascular pathologies. Maximal arterial dimensions were measured using in situ or microCT images. ResultsAngII infusion dramatically augmented aortopathy in Fbn1C1041G/+ mice. Aortic dissection was visible within 3 days of AngII infusion. Over 50% of male Fbn1C1041G/+ mice died during AngII infusion, primarily due to aortic rupture in either the thoracic or abdominal regions. Surviving males had increased ascending and suprarenal aortic diameters and developed pathological lesions at the celiac and superior mesenteric branches of the abdominal aorta. Female mice had a much lower incidence of death but had increased ascending aortic and branch diameters. Although NE infusion also increased systolic blood pressure, it did not affect mortality or enlarge aortic or branch diameters in Fbn1C1041G/+ mice. MicroCT identified novel pathological changes during AngII infusion, including development of aortic branch aneurysms in the celiac and superior mesenteric arteries; however, the maximal diameters of the adjacent suprarenal aorta showed only modest increases in male Fbn1C1041G/+ mice. ConclusionAngII exacerbated aortic pathology in Fbn1C1041G/+ mice. It also promoted development of pathologies at aortic branch points, including the celiac and superior mesenteric arteries.

pathology↗

bioRxiv2025

Cardiac Hemorrhage Precedes Hypertension-induced Fibrosis inPlasminogen Activator Inhibitor-1 Deficient Mice

AimsPlasminogen activator inhibitor-1 (PAI-1) regulates plasmin-mediated proteolysis, thereby influencing vascular stability and tissue remodeling. Angiotensin II (AngII) induces an increase in PAI-1 during the development of ascending thoracic aortic aneurysm (ATAA). The initial purpose of this study was to determine whether deletion of PAI-1 influenced development of ATAA. Subsequently, this study aimed to define the early pathological events preceding cardiac fibrosis in PAI-1 deficiency and the structural domain responsible for its protective effect. Methods and resultsAngII was infused for 4 weeks in whole-body PAI-1 deficient (PAI-1-/-) mice and their wild-type littermates (PAI-1+/+) to examine the role of PAI-1 in ATAA. PAI-1 deficiency did not alter AngII-induced aortopathy but revealed a striking cardiac phenotype characterized by replacement fibrosis predominantly within the epicardium and posterior septum. Ferric iron, indicative of prior hemorrhage, was coincident with fibrosis. Similar phenotypes were observed in PAI-1-/- mice infused with norepinephrine for 4 weeks. To define the pathological events preceding cardiac fibrosis, either AngII or norepinephrine was infused for 1 week in PAI-1+/+ or -/- mice. Both infusions induced extensive epicardial hemorrhage and posterior septal fibrosis in PAI-1-/- mice. To explore the initiation of cardiac pathology, AngII was infused for approximately 1 day. PAI-1-/- mice developed diffuse hemorrhage and cardiomyocyte injury localized to the posterior septum, pathologic changes that preceded overt fibrosis. Finally, to determine the protective domain of PAI-1, saline or AngII was administered to mice harboring loss-of-function point mutations in the protease inhibitory (PAI-1Ala/Ala) or somatomedin B-binding domains (PAI-1AK/AK). Compared to saline infusion, 1 week of AngII induced hemorrhage and heterogeneous fibrosis in PAI-1Ala/Ala, but not PAI-1AK/AK mice. ConclusionsThese findings support that, under hemodynamic stress, PAI-1 deficiency promotes early cardiac hemorrhage and cardiomyocyte injury that lead to fibrosis. Mutational studies implicate dysregulated plasmin generation as an initiator of cardiac injury and fibrosis. TRANSLATIONAL PERSPECTIVECardiac fibrosis has been reported in a human population with PAI-1 deficiency and currently lacks targeted therapy. Our findings demonstrate that in animal models, PAI-1 deficiency confers susceptibility to cardiac injury in response to hemodynamic stress, which may accelerate fibrotic remodeling. Mutational disruption of the protease-inhibitory domain of PAI-1 induced similar pathology, supporting a protective role for this function. These observations suggest that interventions aimed at controlling hypertension, promoting endothelial integrity, or regulating plasmin activation could reduce fibrotic remodeling in this population.

pathology↗

bioRxiv2025

Smooth Muscle Cells and Fibroblasts in the Proximal Thoracic Aorta Exhibit Minor Differences Between Embryonic Origins in Angiotensin II-driven Transcriptional Alterations

BackgroundThoracic aortopathy is influenced by angiotensin II (AngII) and exhibits regional heterogeneity with the proximal region of the thoracic aorta being susceptible. Smooth muscle cells (SMCs) and selected fibroblasts in this region are derived from two embryonic origins: second heart field (SHF) and cardiac neural crest (CNC). While our previous study revealed a critical role of SHF-derived cells in AngII-mediated aortopathy formation, the contribution of CNC-derived cells remains unclear. MethodsMef2c-Cre R26RmT/mG mice were infused with AngII (1,000 ng/kg/min). Proximal thoracic aortas were harvested at baseline or after 3 days of infusion, representing the prepathological phase. Cells were sorted by origins using mGFP (SHF-derived) and mTomato (other origins, nSHF-derived) signals, respectively. After sorting cells by origin, single-cell RNA sequencing was performed and analyzed. ResultsShort-term AngII infusion induced significant transcriptomic changes in both SHF- and nSHF-derived SMCs, but differences between origins were modest. Fibroblast transcriptomes also underwent notable changes by AngII infusion, but differences between SHF and nSHF origins remained modest. Interestingly, AngII infusion resulted in the emergence of a new fibroblast sub-population. Several molecules related to the extracellular matrix, such as Eln and Col3a1, were downregulated in SHF-derived fibroblasts compared to nSHF-derived fibroblasts in the new subcluster. ConclusionFibroblasts in the new subcluster exhibited lineage-specific differences in extracellular matrix-related genes; however, overall transcriptomic differences between origins in SMCs and fibroblasts in response to AngII were modest in the pre-pathological phase of AngII-induced thoracic aortopathy. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/610985v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@17c2e3corg.highwire.dtl.DTLVardef@1bf9517org.highwire.dtl.DTLVardef@d51aedorg.highwire.dtl.DTLVardef@dac951_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2024

Renal Proximal Tubule Cell-specific Megalin Deletion Induces Tubulointerstitial Nephritis in Mice Fed Western Diet

BackgroundPharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice. MethodsFemale Lrp2 f/f mice were bred with male Ndrg1-Cre ERT2 +/0 mice to develop PTC-LRP2 +/+ and -/- littermates. To study atherosclerosis, all mice were bred to an LDL receptor -/- background and fed a Western diet to induce atherosclerosis. ResultsPTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. In contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney. ConclusionsPTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.

pathology↗

bioRxiv2023

β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Young Mice

BACKGROUND{beta}-aminopropionitrile (BAPN) is a pharmacological inhibitor of lysyl oxidase and lysyl oxidase-like proteins. Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice. METHODSBAPN was administered in drinking water for a period ranging from 1 to 12 weeks. The impacts of BAPN were first assessed with regard to dose, strain, age, and sex. BAPN-induced aortic pathological characterization was conducted using histology and immunostaining. To investigate the mechanistic basis of regional heterogeneity, ascending and descending thoracic aortas were harvested after one week of BAPN administration before the appearance of overt pathology. RESULTSBAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta in young C57BL/6J or N mice. No apparent differences were found between male and female mice. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for -smooth muscle actin. One week of BAPN administration compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the two aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. CONCLUSIONSBAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in mice.

pathology↗

bioRxiv2022

Functional Exploration of Conserved Sequences in the Distal Face of Angiotensinogen

BackgroundAngiotensinogen (AGT) is an essential component in the renin-angiotensin system. AGT has highly conserved sequences in the loop and {beta}-sheet regions among species; however, their functions have not been studied. MethodsAdeno-associated viral vector (AAV) serotype 2/8 encoding mouse AGT with mutations of conserved sequences in the loop (AAV.loop-Mut), {beta}-sheet (AAV.{beta}sheet-Mut), or both regions (AAV.loop/{beta}sheet-Mut) were injected into male hepatocyte-specific AGT deficient (hepAGT-/-) mice in an LDL receptor -/- background. AAV containing mouse wild-type AGT (AAV.mAGT) or a null vector (AAV.null) were used as controls. Two weeks after AAV administration, all mice were fed a Western diet for 12 weeks. To determine how AGT secretion is regulated in hepatocytes, AAVs containing the above mutations were transducted into HepG2 cells. ResultsIn hepAGT-/- mice infected with AAV.loop-Mut or {beta}sheet-Mut, plasma AGT concentrations, systolic blood pressure, and atherosclerosis were comparable to those in AAV.mAGT-infected mice. Surprisingly, plasma AGT concentrations, systolic blood pressure, and atherosclerotic lesion size in hepAGT-/- mice infected with AAV.loop/{beta}sheet-Mut were not different from mice infected with AAV.null. In contrast, hepatic Agt mRNA abundance was elevated to a comparable magnitude as AAV.mAGT-infected mice. Immunostaining showed that AGT protein was accumulated trol and AAV containing wild-type mouse AGT as a positive control. We have demonstra ted consistently in this and previous studies tht located in the endoplasmic reticulum. ConclusionsThe conserved sequences in either the loop or {beta}-sheet region individually have no effect on AGT regulation, but the conserved sequences in both regions synergistically contribute to the secretion of AGT from hepatocytes. HIGHLIGHTSO_LIThe loop and {beta}-sheet regions in the distal face of angiotensinogen (AGT) have highly conserved sequences across species. C_LIO_LIMutations on either the loop or {beta}-sheet regions do not affect plasma AGT concentrations, blood pressure, and atherosclerosis in hypercholesterolemic mice. C_LIO_LIThe conserved sequences in the loop and {beta}-sheet regions regulate the secretion of AGT from hepatocytes synergistically in vivo and in cultured cells. C_LI

molecular biology↗

bioRxiv2020

Effects of Endogenous Angiotensin II on Abdominal Aortic Aneurysms and Atherosclerosis in Angiotensin II-infused Mice

Angiotensin II (AngII), a major effector of the renin-angiotensin system, exerts critical roles in regulating vascular function. AngII infusion induces abdominal aortic aneurysms (AAAs) and exacerbates atherosclerosis in hypercholesterolemic mice. We determined the effects of AngII infusion on endogenous AngII regulation and AngII-mediated AAAs and atherosclerosis. AngII infusion increased renal, but not plasma, AngII concentrations in male mice. AngI concentrations were decreased modestly in kidney, but more profoundly in plasma, during AngII infusion. Bovine AngII (DRVYVHPF) has one amino acid difference from mouse AngII (DRVYIHPF) that can be distinguished by LC-MS/MS. Therefore, we determined exogenous versus endogenous peptides in mice infused with bovine AngII. Bovine AngII infusion reduced endogenous renal AngII concentrations. To determine whether the residual endogenous AngII exerted an effect on AAAs and atherosclerosis in mice infused with AngII, aliskiren (a direct renin inhibitor) was administered to AngII-infused male LDL receptor deficient mice. Although aliskiren did not attenuate AAAs in AngII-infused mice, atherosclerotic lesion size was reduced. In conclusion, endogenous AngII concentrations are reduced during AngII infusion but still contribute to atherosclerosis, but not AAA, in AngII-infused hypercholesterolemic mice.

pathology↗

bioRxiv2020

Inhibition of Angiotensin II Dependent AT1a Receptor Stimulation Attenuates Thoracic Aortic Pathology in Fibrillin-1C1041G/+ Mice

Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/127670v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@8e7c32org.highwire.dtl.DTLVardef@7bf57aorg.highwire.dtl.DTLVardef@312d3forg.highwire.dtl.DTLVardef@9198bd_HPS_FORMAT_FIGEXP M_FIG C_FIG ObjectiveA cardinal feature of Marfan syndrome is thoracic aortic aneurysm (TAA). The contribution of ligand-dependent stimulation of angiotensin II receptor type 1a (AT1aR) to TAA progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacologic modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on TAA in mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+). Approach and ResultsTAA in Fbn1C1041G/+ mice were determined in both sexes and found to be strikingly sexual dimorphic. Males displayed progressive dilation over 12 months while ascending aortic dilation in Fbn1C1041G/+ females did not differ significantly from wild type mice. To determine the role of AT1aR, Fbn1C1041G/+ mice that were either +/+ or -/- for AT1aR were generated. AT1aR deletion reduced progressive expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen (AGT-ASO) was administered to male Fbn1C1041G/+ mice to determine the effects of angiotensin II depletion. AGT-ASO administration, at doses that markedly reduced plasma AGT concentrations, attenuated progressive dilation of the ascending aorta and aortic root. AGT-ASO also reduced medial thickening and elastin fragmentation. ConclusionsGenetic approaches to delete AT1aR and deplete AngII production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1C1041G/+ mice. These data are consistent with ligand (AngII) dependent stimulation of AT1aR being responsible for aortic disease progression. HighlightsO_LIProfound sexual dimorphism of aortic disease occurs in Fbn1C1041G/+ mice, with female mice being more resistant and male mice being more susceptible. C_LIO_LIInhibition of the AngII-AT1aR axis attenuates aortic pathology in male Fbn1C1041G/+ mice. C_LIO_LIAntisense oligonucleotides targeting angiotensinogen deplete plasma angiotensinogen and attenuate thoracic aortic aneurysms. C_LI

physiology↗

bioRxiv2020

Ultrasound Monitoring of Descending Aortic Aneurysms and Dissections in Mice

Several modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound, are available to visualize mouse aortas.1-3 CT and MRI enable us to obtain reliable images of the aorta and its branches. However, CT requires vascular contrast and MRI is procedurally complex. Thus, these modalities are used only occasionally for in vivo monitoring of mouse studies. High frequency ultrasonography is a common approach for aortic monitoring in mice.4 The standard ultrasound approach using a para-sternal view can visualize the aortic root, ascending aorta, and aortic arch, while this approach cannot visualize the descending region due to the presence of lungs and ribs. Therefore, the ability to perform in vivo monitoring of descending aortic diseases in mice has been an impediment. This study reports a para-spinal dorsal approach for ultrasound imaging of mouse descending aortas.

pathology↗

bioRxiv2020

Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice

BACKGROUNDCytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix (ECM) with contractile filaments. During AAA development, (i) aortic medial degeneration is associated with loss of smooth muscle cell (SMC) integrity, and (ii) fibrogenic mesenchymal cells (FMSCs) mediates ECM remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Angiotensin II (AngII)-induced AAAs in low density receptor deficient (LDLR-/-) mice. OBJECTIVESTo evaluate the functional contribution of FMSCs-derived calpain-2 on (i) cytoskeletal structural protein and ECM alterations, and (ii) AAA progression. METHODSCalpain-2 protein, and cytoskeletal protein (e.g. filamin or talin) fragmentation in human and mice AAA tissues were assessed by immunohistochemical and western blot analyses. LDLR-/- mice that were either inducible-whole body or FMSC-specific calpain-2 deficient were fed a fat-enriched diet and infused with AngII for 4 weeks. The association of cytoskeletal protein to ECM was evaluated using aortic SMCs, in vitro. In addition, the effect of calpain-2 deficiency on the stability of established AAA was examined. RESULTSCalpain-2 protein, and filamin/talin fragmentation are significantly elevated in AAAs. Ubiquitous or FMSC-specific depletion of calpain-2 suppressed AngII-induced AAAs, filamin/talin fragmentation and promoted ECM protein, collagen. Calpain-2 silencing in SMCs reduced AngII-induced filamin/talin fragmentation. In addition, silencing of filamin or talin in SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed established AAA rupture. CONCLUSIONCalpain-2 activation promotes cytoskeletal structural protein fragmentation and ECM degradation of experimental AAA aortas. Treatment with calpain-2 specific inhibitor may facilitate the clinical management of AAA.

pathology↗

bioRxiv2020

Functional Importance of Second Heart Field-derived Cells During Thoracic Aortic Aneurysm Formation

BackgroundThe ascending aorta is a common location for aneurysm and dissection. This aortic region is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field (SHF) or the cardiac neural crest. SHF-derived cells populate areas that coincide with the spatial specificity of thoracic aortopathies. The purpose of this study was to determine whether and how SHF-derived cells contribute to ascending aortopathies. MethodsAscending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin II (AngII)-infused mice. Ascending aortas without overt pathology from AngII-infused mice were subjected to mass spectrometry assisted proteomics, and molecular features of SHF-derived cells were determined by single cell transcriptomic analyses. Genetic deletion of either low-density lipoprotein receptor-related protein 1 (Lrp1) or transforming growth factor-{beta} receptor 2 (Tgfbr2) in SHF- derived cells was conducted to examine the impact of SHF-derived cells on vascular integrity. ResultsPathologies in human ascending aortic aneurysmal tissues were predominant in outer medial layers and adventitia. This gradient was mimicked in mouse aortas following AngII infusion that was coincident with the distribution of SHF-derived cells. Proteomics indicated that brief AngII infusion, prior to overt pathology, evoked downregulation of SMC proteins and differential expression of extracellular matrix proteins, including several LRP1 ligands. LRP1 deletion in SHF-derived cells augmented AngII-induced ascending aortic aneurysm and rupture. Single cell transcriptomic analysis revealed that brief AngII infusion decreased Lrp1 and Tgfbr2 mRNA abundance in SHF-derived cells and induced a unique fibroblast population with low abundance of Tgfbr2 mRNA. SHF-specific Tgfbr2 deletion led to embryonic lethality at E12.5 with dilatation of the outflow tract and retroperitoneal hemorrhage. Integration of proteomic and single cell transcriptomics results identified plasminogen activator inhibitor 1 (PAI1) as the most increased protein in SHF-derived SMCs and fibroblasts during AngII infusion. Immunostaining revealed a transmural gradient of PAI1 in both ascending aortas of AngII-infused mice and human ascending aneurysmal aortas that mimicked the gradient of medial and adventitial pathologies. ConclusionSHF-derived cells exert a critical role in maintaining vascular integrity through LRP1 and TGF-{beta} signaling associated with increases of aortic PAI1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/930917v6_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@185e3d9org.highwire.dtl.DTLVardef@131d702org.highwire.dtl.DTLVardef@11afa42org.highwire.dtl.DTLVardef@242786_HPS_FORMAT_FIGEXP M_FIG C_FIG Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABS- SHF-derived SMCs and fibroblasts associate with AngII-induced aortic pathologies. - AngII induces a distinct fibroblast sub-cluster that is less abundant for mRNAs related to major extracellular components and TGF{beta} ligands and receptors, but more abundant for proliferative genes. - TGFBR2 deletion in SHF-derived cells are embryonic lethal with significant dilatation of the outflow tract in mice. - SHF-specific deletion of LRP1 leads to aortic pathologies in mice, supporting the importance of SHF-derived cells in maintaining ascending aortic wall integrity. What are the clinical implications?- Heterogeneity of the embryonic origins of SMCs and fibroblasts contributes to complex mechanisms of vasculopathy formation, which should be considered when investigating the pathogenesis of thoracic aortopathies.

pathology↗

bioRxiv2020

Hypercholesterolemia Accelerates the Initiation and Progression of Angiotensin II-induced Abdominal Aortic Aneurysms

ObjectiveThis study determined whether hypercholesterolemia would contribute to both the initiation and progression of angiotensin (Ang)II-induced abdominal aortic aneurysms (AAAs) in mice. Methods and ResultsTo determine whether hypercholesterolemia accelerates the initiation of AAAs, male low-density lipoprotein (LDL) receptor -/- mice were either fed one week of Western diet prior to starting AngII infusion or initiated Western diet one week after starting AngII infusion. During the first week of AngII infusion, mice fed normal diet had less luminal expansion of the suprarenal aorta compared to those initiated Western diet after the first week of AngII infusion. The two groups achieved comparable luminal dilation on week 2 through week 6 of AngII infusion as monitored by ultrasound. To determine whether hypercholesterolemia contributed to the progression of established AAAs, male LDL receptor -/- mice were fed Western diet and infused with AngII for 4 weeks. Mice with established AAAs were then stratified into two groups based on luminal diameters measured by ultrasound. While AngII infusion was continued for another 8 weeks in both groups, mice in one group were continuously fed Western diet, but diet in the other group was switched to normal laboratory diet. In the latter group, plasma cholesterol concentrations were reduced rapidly to approximately 500 mg/dl within one week after the diet was switched from Western diet to normal laboratory diet. Luminal expansion progressed constantly in mice continuously fed Western diet, whereas no continuous expansion was detected in mice that were switched to normal laboratory diet. ConclusionsHypercholesterolemia accelerates both the initiation of AAAs and progression of established AAAs in AngII-infused male LDL receptor -/- mice. Clinical RelevanceHypercholesterolemia is modestly associated with AAAs in observational or retrospective clinical studies. It is not feasible to study whether hypercholesterolemia contributes to the initiation of AAAs or progression of established AAAs in human. This study using AngII-induced AAA mouse model provides solid evidence that hypercholesterolemia contributes to both the initiation and progression of AAAs, supporting that statin therapy at any stage of AAA development may be beneficial to hypercholesterolemic patients with AAAs.

pathology↗

bioRxiv2019

The Two Amino Acids Proximate to the Renin Cleavage Site of Human Angiotensinogen Do Not Affect Angiotensin II-mediated Functions in Mice

ObjectiveRenin cleavage of angiotensinogen (AGT) has species specificity. Since the residues at positions 11 and 12 of AGT are different between human and mouse AGT, we determined whether these two residues in AGT affect renin cleavage and angiotensin II-mediated functions using an adeno-associated viral (AAV) approach for manipulating AGT in vivo. Approach and ResultsHepatocyte-specific AGT deficient (hepAGT-/-) mice in an LDL receptor -/- background were infected with AAVs containing a null insert, human AGT, or mouse AGT expressing the same residues of the human protein at positions 11 and 12 [mouse AGT (L11V;Y12I)]. Expression of human AGT in hepAGT-/- mice led to high plasma human AGT concentrations without changes in plasma mouse endogenous AGT, plasma renin concentrations, blood pressure, or atherosclerosis. This is consistent with human AGT not being cleaved by mouse renin. To determine whether the residues at positions 11 and 12 in human AGT lead to the inability of mouse renin to cleave human AGT, hepAGT-/- mice were injected with AAV encoding mouse AGT (L11V;Y12I). Expression of mouse AGT (L11V;Y12I) resulted in increased plasma mouse AGT concentrations, reduced renin concentrations, and increased renal AngII concentrations that were comparable to their concentrations in hepAGT+/+ mice. This mouse AGT variant increased blood pressure and atherosclerosis in hepAGT-/- mice to the magnitude of hepAGT+/+ mice. ConclusionReplacement of L11 and Y12 to V11 and I12, respectively, in mouse AGT does not affect renin cleavage and AngII-mediated functions in mice. HIGHLIGHTSO_LIHuman AGT is not cleaved by mouse renin and does not change AngII-mediated functions in hepatocyte-specific AGT -/- mice. C_LIO_LIReplacement of the N-terminal amino acids at 11 and 12 positions from mouse to human AGT does not affect renin cleavage and AngII-mediated functions in hepatocyte-specific AGT -/- mice. C_LI

pathology↗