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AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agtin mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agthas been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.

There are many metrics to evaluate the performance and status of journals. Among these, the journal impact factor (JIF) has become the dominant metric. The influence of JIF is illustrated by its widespread use to evaluate academic status, compensation, and funding decisions. However, as noted by Clarivate Analytics, the parent company of the Web of Science (WoS), the JIF should not be used without careful attention to the many phenomena that influence citation rates. To facilitate transparency, Clarivate Analytics provides all data used to determine the JIF. In addition, WoS provides other metrics for journal evaluation, including the article citation median and the review citation median. These metrics are represented as medians to minimize the confounding influence of a small number of highly cited articles that may occur when data are represented as means. Another feature of these WoS metrics is that data are separated according to different publication types of article (original research and review). To systematically compare these selected metrics, we used the data provided on the WoS web site to analyze 25 top ranked cardiovascular journals in the same mode as represented in the WoS citation distribution window. The results indicate that the article citation median and review citation median overcome several concerns that have been raised about the JIF and seem to provide enhanced objectivity as an indicator of journal impact in publishing original research and reviews. Therefore, we advocate that these additional WoS metrics might be preferentially considered as indicators of journal performance.

Supplemental Digital Content is available in the text.AngII (angiotensin II) infusion in mice has been used to provide mechanistic insight into human abdominal aortic aneurysms for over 2 decades. This is a technically facile animal model that recapitulates multiple facets of the human disease. Although numerous publications have reported abdominal aortic aneurysms with AngII infusion in mice, there remain many fundamental unanswered questions such as uniformity of describing the pathological characteristics and which cell type is stimulated by AngII to promote abdominal aortic aneurysms. Extrapolation of the findings to provide insight into the human disease has been hindered by the preponderance of studies designed to determine the effects on initiation of abdominal aortic aneurysms, rather than a more clinically relevant scenario of determining efficacy on the established disease. The purpose of this review is to enhance understanding of AngII-induced abdominal aortic pathologies in mice, thereby providing greater insight into the human disease.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Aortic structure and function are controlled by the coordinated actions of different aortic cells and the extracellular matrix. Several pathways have been identified that control the aortic wall in a cell-type–specific manner and play diverse roles in various phases of aortic injury, repair, and remodeling. This complexity of signaling in the aortic wall poses challenges to the development of therapeutic strategies for treating aortic aneurysms and dissections. Here, in part II of this Recent Highlights series on aortic aneurysms and dissections, we will summarize recent studies published in Arteriosclerosis, Thrombosis, and Vascular Biologythat have contributed to our knowledge of the signaling pathway–related mechanisms of aortic aneurysms and dissections.

The aortic wall is composed of highly dynamic cell populations and extracellular matrix. In response to changes in the biomechanical environment, aortic cells and extracellular matrix modulate their structure and functions to increase aortic wall strength and meet the hemodynamic demand. Compromise in the structural and functional integrity of aortic components leads to aortic degeneration, biomechanical failure, and the development of aortic aneurysms and dissections (AAD). A better understanding of the molecular pathogenesis of AAD will facilitate the development of effective medications to treat these conditions. Here, we summarize recent findings on AAD published in ATVB. In this issue, we focus on the dynamics of aortic cells and extracellular matrix in AAD; in the next issue, we will focus on the role of signaling pathways in AAD.

Nonalcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that the renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of the RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here, we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT+/+) and hepatocyte-specific AGT-deficient mice (hepAGT−/−) were fed a Western diet and a normal laboratory diet for 12 weeks, respectively. Compared with hepAGT+/+mice, Western diet-fed hepAGT−/−mice gained less body weight with improved insulin sensitivity. The attenuated severity of liver steatosis in hepAGT−/−mice was evidenced by histologic changes and reduced intrahepatic triglycerides. The abundance of SREBP1 and its downstream molecules, acetyl-CoA carboxylase and FASN, was suppressed in hepAGT−/−mice. Furthermore, serum derived from hepAGT+/+mice stimulated hepatocyte SREBP1 expression, which could be diminished by protein kinase B (Akt)/mammalian target of rapamycin (mTOR) inhibition in vitro. Administration of losartan did not affect diet-induced body weight gain, liver steatosis severity, and hepatic p-Akt, p-mTOR, and SREBP1 protein abundance in hepAGT+/+mice. These data suggest that attenuation of Western diet-induced liver steatosis in hepAGT−/−mice is associated with the alternation of the Akt/mTOR/SREBP-1c pathway.

Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender disparities were prevalent in many institutions, recent decades have witnessed significant progress in supporting the career advancement of women faculty in science and academic medicine. However, continued advancement is necessary as previously unrecognized needs and new opportunities for improvement emerge. To identify the needs, opportunities, and potential challenges encountered by women faculty, the Women’s Leadership Committee of the Arteriosclerosis, Thrombosis, and Vascular Biology Council developed an initiative termed GROWTH (Generating Resources and Opportunities for Women in Technology and Health). The committee designed a survey questionnaire and interviewed 19 leaders with roles and responsibilities in faculty development from a total of 12 institutions across various regions of the United States. The results were compiled, analyzed, and discussed. Based on our interviews and analyses, we present the current status of these representative institutions in supporting faculty development, highlighting efforts specific to women faculty. Through the experiences, insights, and vision of these leaders, we identified success stories, challenges, and future priorities. Our article provides a primer and a snapshot of institutional efforts to support the advancement of women faculty. Importantly, this article can serve as a reference and resource for academic entities seeking ideas to gauge their commitment level to women faculty and to implement new initiatives. Additionally, this article can provide guidance and strategies for women faculty as they seek support and resources from their current or prospective institutions when pursuing new career opportunities.

Supplemental Digital Content is available in the text.

The renin-angiotensin system (RAS) is an essential hormonal system involved in water and sodium reabsorption, renal blood flow regulation, and arterial constriction. Systemic stimulation of the RAS with infusion of the main peptide angiotensin II (Ang II) in animals as well as pathological elevation of renin (i.e renovascular hypertension) to increase circulatory Ang II in humans ultimately lead to hypertension and end-organ damage. In addition to hypertension, accumulating evidence support that the Ang II type 1 receptor exerts a critical role in cardiovascular and kidney diseases independent of blood pressure elevation. In the last two decades, the identification of an increased number of peptides and receptors has facilitated the concept that the RAS has both detrimental and beneficial effects on the cardiovascular system depending on which RAS components are activated. For example, angiotensin 1-7 and Ang II type 2 receptors act as a counter-regulatory system against the classical RAS by mediating vasodilation. While the RAS as an endocrine system for regulation of blood pressure is well established, there remain many unanswered questions and controversial findings regarding blood pressure regulation and pathophysiological regulation of cardiovascular diseases at the tissue level. This review article will include the latest knowledge gleaned from cell type-selective gene deleted mice regarding cell type-specific roles of AngII receptors and discuss their significance in health and diseases. In particular, we focus on the roles of these receptors expressed in vascular, cardiac, and kidney epithelial cells.

Introduction:Ascending thoracic aortic aneurysm (ATAA) progression to dissection (ATAD) is associated with a high risk of mortality. Since the specific molecular and cellular changes leading to dissection are poorly understood, we compared transcriptome profiles of aortic smooth muscle cells (SMCs) between ATAD, ATAA, and controls.Methods:We performed single-cell RNA sequencing (scRNA-seq) of ascending aorta tissues from patients with acute ATAD (dissected and non-dissected areas were collected separately, 3 women, 5 men) and ATAA without dissection (3 women, 4 men), and from control subjects without aortic diseases (transplant donors, 3 women, 5 men). SMCs clusters were analyzed and immunofluorescence staining was performed to confirm expression of key genes. Mice exposed to β-aminopropionitrile monofumarate (BAPN) starting at P21 were used to investigate the changes of mitochondria-related genes during disease progression in undissected mice.Results:Compared with controls, SMCs in ATAA exhibited an adaptive response characterized by upregulation of a subset of focal adhesion and contractile genes and a pro-fibroblast phenotype. These expression changes were decreased in SMCs in ATAD, which instead exhibited significant increases in genes for inflammatory response, glycolysis, senescence and cell death. Additionally, mitochondrial genes including tricarboxylic acid (TCA) cycle genes (e.g. SDHB, FH, and MDH2) and mitochondria genome genes (e.g. MT-ND4, MT-CO2, and MT-CYB), exhibited increased expression in ATAAs, and downregulated in ATADs. Immunofluorescence staining of corresponding proteins confirmed some key findings. Consistent with human data, scRNA-seq showed increased mitochondria-related genes in SMCs in BAPN mouse model at P35 when aneurysms form, which were decreased in the proximal aortic tissues after the onset of dissection deaths in surviving mice at P42.Conclusions:Our data suggest a dynamic change from mitochondrial compensation to failure with progression from normal to aortic aneurysms to dissections, which ultimately increases cell death pathways.

Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-ß regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-?B–mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II–induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.

Introduction: The mechanism of tumorigenesis and metastasis of ovarian cancer has not yet been elucidated. This study aimed to investigate the role and molecular mechanism of cytosolic nonspecific dipeptidase 2 in tumorigenesis and metastasis.Methods: Cytosolic nonspecific dipeptidase 2 expression in human ovarian cancer tissues and cell lines was assessed with methyl thiazolyl tetrazolium (MTT), clone formation, and transwell assays performed to evaluate the ability of ovarian cancer cells to proliferate and migrate. Nude mice tumor formation experiments were also performed by subcutaneously injecting cells with stable cytosolic nonspecific dipeptidase 2 knockdown and control SKOV3 cells into BALB/c female nude mice to detect changes in PI3K/AKT pathway-related proteins by Western blotting.Results: Cytosolic nonspecific dipeptidase 2 was highly expressed in human ovarian cancer tissues, with its expression associated with pathological data, including ovarian cancer metastasis. A cytosolic nonspecific dipeptidase 2 stable knockdown or ectopic expression ovarian cancer cell model was established and demonstrated that cytosolic nonspecific dipeptidase 2 could promote the proliferation of ovarian cancer cells. Transwell cell migration and invasion assays confirmed that cytosolic nonspecific dipeptidase 2 enhanced cell metastasis in ovarian cancer. Furthermore, in vivoxenograft experiments demonstrated that cytosolic nonspecific dipeptidase 2 can promote the development and progression of ovarian cancer, increasing the expression of phosphorylated PI3K and AKT.Conclusions: Cytosolic nonspecific dipeptidase 2 promotes the occurrence and development of ovarian cancer through the PI3K/AKT signaling pathway.