scholarly journals Angiogenic Secretion Profile of Valvular Interstitial Cells Varies With Cellular Sex and Phenotype

2021 ◽  
Vol 8 ◽  
Author(s):  
Victoria Nelson ◽  
Vaidehi Patil ◽  
LaTonya R. Simon ◽  
Kelsey Schmidt ◽  
Chloe M. McCoy ◽  
...  
Keyword(s):  
Sex Differences ◽  
Sexual Dimorphism ◽  
Aortic Valve Disease ◽  
Disease Process ◽  
Interstitial Cells ◽  
Fibroblast Growth ◽  
Valvular Interstitial Cells ◽  
Angiogenic Growth Factors ◽  
Related Factors ◽  
Secretion Profile

Angiogenesis is a hallmark of fibrocalcific aortic valve disease (CAVD). An imbalance of pro- and anti-angiogenic factors is thought to play a role in driving this disease process, and valvular interstitial cells (VICs) may act as a significant source of these factors. CAVD is also known to exhibit sexual dimorphism in its presentation, and previous work suggested that VICs may exhibit cellular-scale sex differences in the context of angiogenesis. The current study sought to investigate the production of angiogenesis-related factors by male and female VICs possessing quiescent (qVIC) or activated (aVIC) phenotypes. Production of several pro-angiogenic growth factors was elevated in porcine aVICs relative to qVICs, with sex differences found in both the total amounts secreted and their distribution across media vs. lysate. Porcine valvular endothelial cells (VECs) were also sex-separated in culture and found to behave similarly with respect to metabolic activity, viability, and tubulogenesis, but male VECs exhibited higher proliferation rates than female VECs. VECs responded to sex-matched media conditioned by VICs with increased tubulogenesis, but decreased proliferation, particularly upon treatment with aVIC-derived media. It is likely that this attenuation of proliferation resulted from a combination of decreased basic fibroblast growth factor and increased thrombospondin-2 (TSP2) secreted by aVICs. Overall, this study indicates that VICs regulate angiogenic VEC behavior via an array of paracrine molecules, whose secretion and sequestration are affected by both VIC phenotype and sex. Moreover, strong sex differences in TSP2 secretion by VICs may have implications for understanding sexual dimorphism in valve fibrosis, as TSP2 is also a powerful regulator of fibrosis.

scholarly journals Fibroblast growth factor represses Smad‐mediated myofibroblast activation in aortic valvular interstitial cells

2008 ◽  
Vol 22 (6) ◽  
pp. 1769-1777 ◽  
Author(s):  
Melinda C. Cushing ◽  
Peter D. Mariner ◽  
Jo‐Tsu Liao ◽  
Evan A. Sims ◽  
Kristi S. Anseth
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Interstitial Cells ◽  
Fibroblast Growth ◽  
Valvular Interstitial Cells

Abstract 15192: Leptin Effects on Osteoblast Differentiation of Human Valvular Interstitial Cells: New Insight Into Calcific Aortic Valve Disease

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Mickael Rosa ◽  
Rodrigo Lorenzi ◽  
Madjid Tagzirt ◽  
Francis Juthier ◽  
Antoine Rauch ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Osteoblast Differentiation ◽  
Interstitial Cells ◽  
Valve Disease ◽  
Calcium Deposition ◽  
Valvular Interstitial Cells ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Alp Activity

Introduction: Calcific aortic valve disease (CAVD) affects 2% to 6% of the population over 65 years and results from dysregulated processes such as calcification, supported in part by the osteoblast differentiation of valvular interstitial cells (VIC), the most prevalent cell type in the human aortic valves. Leptin has recently been linked to aortic valve calcification in ApoE-/- mice. Hypothesis: Our hypothesis is that leptin could play a role in the calcifying processes implicated in CAVD via direct effects on human VIC. Methods: Patients who underwent aortic valve replacement for severe CAVD (n=43) or with coronary artery disease (CAD) but without CAVD (n=129) were included in this study. Presence of leptin was analyzed in human explanted calcified aortic valves and blood samples. Leptin receptors expression was analyzed in aortic valves and VIC isolated from aortic valves. Leptin effects on osteoblast differentiation of VIC in presence or not of Akt and ERK inhibitors were investigated by alizarin red staining, alkaline phosphatase (ALP) activity, and RT-qPCR analysis for osteopontin, ALP, bone morphogenetic protein BMP-2, and RUNX2. Results: Patients with CAVD have significant higher serum leptin concentration than CAD patients (p=0.002). The presence of leptin was observed by immunochemistry in human calcified aortic valves, with higher concentrations in calcified vs non-calcified zones (p=0.01). Both short and long leptin receptor isoforms were expressed in VIC. Chronic leptin stimulation of VIC enhanced ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. This treatment led to a higher, dose dependent, ALP activity and calcium deposition in VIC. Inhibiting Akt or ERK during leptin stimulation led to a reduced calcification by bringing the expression of calcification genes to the control levels. Conclusions: Together, these novel findings depict the potential role of leptin in the process of CAVD by triggering calcification processes in human VIC.

scholarly journals Heme-Mediated Activation of the Nrf2/HO-1 Axis Attenuates Calcification of Valve Interstitial Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 427
Author(s):  
Enikő Balogh ◽  
Arpan Chowdhury ◽  
Haneen Ababneh ◽  
Dávid Máté Csiki ◽  
Andrea Tóth ◽  
...  
Keyword(s):  
Target Gene ◽  
Interstitial Cells ◽  
Protective Role ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Valvular Interstitial Cells ◽  
Aortic Valves ◽  
Antioxidant Genes ◽  
Valve Interstitial Cells ◽  
Nrf2 Target Gene

Calcific aortic valve stenosis (CAVS) is a heart disease characterized by the progressive fibro-calcific remodeling of the aortic valves, an actively regulated process with the involvement of the reactive oxygen species-mediated differentiation of valvular interstitial cells (VICs) into osteoblast-like cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of a variety of antioxidant genes, and plays a protective role in valve calcification. Heme oxygenase-1 (HO-1), an Nrf2-target gene, is upregulated in human calcified aortic valves. Therefore, we investigated the effect of Nrf2/HO-1 axis in VIC calcification. We induced osteogenic differentiation of human VICs with elevated phosphate and calcium-containing osteogenic medium (OM) in the presence of heme. Heme inhibited Ca deposition and OM-induced increase in alkaline phosphatase and osteocalcin (OCN) expression. Heme induced Nrf2 and HO-1 expression in VICs. Heme lost its anti-calcification potential when we blocked transcriptional activity Nrf2 or enzyme activity of HO-1. The heme catabolism products bilirubin, carbon monoxide, and iron, and also ferritin inhibited OM-induced Ca deposition and OCN expression in VICs. This study suggests that heme-mediated activation of the Nrf2/HO-1 pathway inhibits the calcification of VICs. The anti-calcification effect of heme is attributed to the end products of HO-1-catalyzed heme degradation and ferritin.

scholarly journals Regulatory Role of Sex Hormones in Cardiovascular Calcification

2021 ◽  
Vol 22 (9) ◽  
pp. 4620
Author(s):  
Holly J. Woodward ◽  
Dongxing Zhu ◽  
Patrick W. F. Hadoke ◽  
Victoria E. MacRae
Keyword(s):  
Cardiovascular Disease ◽  
Sex Differences ◽  
Sexual Dimorphism ◽  
Aortic Stenosis ◽  
Sex Hormones ◽  
Sex Hormone ◽  
Increased Risk ◽  
Male Sex ◽  
Primary Male

Sex differences in cardiovascular disease (CVD), including aortic stenosis, atherosclerosis and cardiovascular calcification, are well documented. High levels of testosterone, the primary male sex hormone, are associated with increased risk of cardiovascular calcification, whilst estrogen, the primary female sex hormone, is considered cardioprotective. Current understanding of sexual dimorphism in cardiovascular calcification is still very limited. This review assesses the evidence that the actions of sex hormones influence the development of cardiovascular calcification. We address the current question of whether sex hormones could play a role in the sexual dimorphism seen in cardiovascular calcification, by discussing potential mechanisms of actions of sex hormones and evidence in pre-clinical research. More advanced investigations and understanding of sex hormones in calcification could provide a better translational outcome for those suffering with cardiovascular calcification.

scholarly journals Sex Differences in the Triad of Acquired Sensorineural Hearing Loss

2021 ◽  
Vol 22 (15) ◽  
pp. 8111
Author(s):  
Kuang-Hsu Lien ◽  
Chao-Hui Yang
Keyword(s):  
Hearing Loss ◽  
Sex Differences ◽  
Sexual Dimorphism ◽  
Sensorineural Hearing Loss ◽  
Hormone Replacement ◽  
Modern Society ◽  
Sensorineural Hearing ◽  
Drug Induced ◽  
Age Related ◽  
Age Related Hearing Loss

The triad of noise-generated, drug-induced, and age-related hearing loss is the major cause of acquired sensorineural hearing loss (ASNHL) in modern society. Although these three forms of hearing loss display similar underlying mechanisms, detailed studies have revealed the presence of sex differences in the auditory system both in human and animal models of ASNHL. However, the sexual dimorphism of hearing varies among noise-induced hearing loss (NIHL), ototoxicity, and age-related hearing loss (ARHL). Importantly, estrogen may play an essential role in modulating the pathophysiological mechanisms in the cochlea and several reports have shown that the effects of hormone replacement therapy on hearing loss are complex. This review will summarize the clinical features of sex differences in ASNHL, compare the animal investigations of cochlear sexual dimorphism in response to the three insults, and address how estrogen affects the auditory organ at molecular levels.

scholarly journals Sexual conflict drives micro- and macroevolution of sexual dimorphism in immunity

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Basabi Bagchi ◽  
Quentin Corbel ◽  
Imroze Khan ◽  
Ellen Payne ◽  
Devshuvam Banerji ◽  
...  
Keyword(s):  
Sex Differences ◽  
Sexual Dimorphism ◽  
Mating System ◽  
Sexual Conflict ◽  
Experimental Evolution ◽  
Parasitic Infections ◽  
Pathogen Dynamics ◽  
Trade Offs ◽  
Host Pathogen ◽  
Seed Beetles

Abstract Background Sexual dimorphism in immunity is believed to reflect sex differences in reproductive strategies and trade-offs between competing life history demands. Sexual selection can have major effects on mating rates and sex-specific costs of mating and may thereby influence sex differences in immunity as well as associated host–pathogen dynamics. Yet, experimental evidence linking the mating system to evolved sexual dimorphism in immunity are scarce and the direct effects of mating rate on immunity are not well established. Here, we use transcriptomic analyses, experimental evolution and phylogenetic comparative methods to study the association between the mating system and sexual dimorphism in immunity in seed beetles, where mating causes internal injuries in females. Results We demonstrate that female phenoloxidase (PO) activity, involved in wound healing and defence against parasitic infections, is elevated relative to males. This difference is accompanied by concomitant sex differences in the expression of genes in the prophenoloxidase activating cascade. We document substantial phenotypic plasticity in female PO activity in response to mating and show that experimental evolution under enforced monogamy (resulting in low remating rates and reduced sexual conflict relative to natural polygamy) rapidly decreases female (but not male) PO activity. Moreover, monogamous females had evolved increased tolerance to bacterial infection unrelated to mating, implying that female responses to costly mating may trade off with other aspects of immune defence, an hypothesis which broadly accords with the documented sex differences in gene expression. Finally, female (but not male) PO activity shows correlated evolution with the perceived harmfulness of male genitalia across 12 species of seed beetles, suggesting that sexual conflict has a significant influence on sexual dimorphisms in immunity in this group of insects. Conclusions Our study provides insights into the links between sexual conflict and sexual dimorphism in immunity and suggests that selection pressures moulded by mating interactions can lead to a sex-specific mosaic of immune responses with important implications for host–pathogen dynamics in sexually reproducing organisms.

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