Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms

Torres-Estay, Verónica; Carreño, Daniela V.; Fuenzalida, Patricia; Watts, Anica; Francisco, Ignacio F. San; Montecinos, Viviana P.; Sotomayor, Paula; Ebos, John M.L.; Smith, Gary J.; Godoy, Alejandro

doi:10.1007/s10456-016-9525-6

Cited by 36 publications

(24 citation statements)

References 48 publications

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“…AR, identified on EC of multiple organs in humans, including brain, heart, umbilical vein, dermis, salivary gland and bone, as well as prostate, ovary and myometrium (Torres‐Estay et al . , ), has been implicated as mediating angiogenesis in both sexes (Yoshida et al . ).…”

Section: Discussionmentioning

confidence: 99%

Sex differences influencing micro‐ and macrovascular endothelial phenotype in vitro

Huxley

Kemp

Schramm

et al. 2018

The Journal of Physiology

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Vascular endothelial cells (EC) are heterogeneous with respect to phenotype, reflecting at least the organ of origin, location within the vascular network and physical forces. As an independent influence on EC functions in health or aetiology, susceptibility, and progression of dysfunction in numerous disease states, sex has been largely ignored. The present study focussed on EC isolated from aorta (macrovascular) and skeletal muscle vessels (microvascular) of age-matched male and female rats under identical conditions of short-term (passage 4) culture. We tested the hypothesis that genomic sex would not influence endothelial growth, wound healing, morphology, lactate production, or messenger RNA and protein expression of key proteins (sex hormone receptors for androgen and oestrogens α and β; platelet endothelial cell adhesion molecule-1 and vascular endothelial cadherin mediating barrier function; α β and N-cadherin influencing matrix interactions; intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 mediating EC/white cell adhesion). The hypothesis was rejected because the EC origin (macro- vs. microvessel) and sex influenced multiple phenotypic characteristics. Statistical model analysis of EC growth demonstrated an hierarchy of variable importance, recapitulated for other phenotypic characteristics, with predictions assuming EC homogeneity < sex < vessel origin < sex and vessel origin. Furthermore, patterns of EC mRNA expression by vessel origin and by sex did not predict protein expression. Overall, the present study demonstrated that accurate assessment of sex-linked EC dysfunction first requires an understanding of EC function by position in the vascular tree and by sex. The results from a single EC tissue source/species/sex cannot provide universal insight into the mechanisms regulating in vivo endothelial function in health, and no less in disease.

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Section: Discussionmentioning

confidence: 99%

Sex differences influencing micro‐ and macrovascular endothelial phenotype in vitro

Huxley

Kemp

Schramm

et al. 2018

The Journal of Physiology

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“…Structurally, mPTP is generated as one contiguous pore spanning the intermembrane space by the apposition of the voltage-dependent anion channel (VDAC) within the outer membrane and the adenine nucleotide translocator (ANT) within the inner membrane, regulated by CypD within the mitochondrial matrix. Notably, recent observations indicate that CypD can undergo covalent modifications, 51 and phosphorylated CypD is associated with an increased susceptibility to mPTP opening. 52 In our study, HR treatment had no effect on VDAC, ANT, and CypD expression ( Figure 5D-G); however, the phosphorylation of Ser31 by CypD was significantly increased in response to HR injury but was statistically decreased to normal levels by melatonin through abrogating Ripk3 activation ( Figure 5E and H).…”

Section: Ripk3 Evokes Endothelial Necroptosis Via Inducing Cypd Phomentioning

confidence: 99%

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

Zhou

Zhu

et al. 2018

Journal of Pineal Research

204

168

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The molecular features of necroptosis in cardiac ischemia-reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms, and microvascular perfusion defects. However, administration of melatonin prevented Ripk3 activation and provided a pro-survival advantage for the endothelial system in the context of cardiac IR injury, similar to the results obtained via genetic ablation of Ripk3. Functional investigations clearly illustrated that activated Ripk3 upregulated PGAM5 expression, and the latter increased CypD phosphorylation, which obligated endothelial cells to undergo necroptosis via augmenting mPTP (mitochondrial permeability transition pore) opening. Interestingly, melatonin supplementation suppressed mPTP opening and interrupted endothelial necroptosis via blocking the Ripk3-PGAM5-CypD signal pathways. Taken together, our studies identified the Ripk3-PGAM5-CypD-mPTP axis as a new pathway responsible for reperfusion-mediated microvascular damage via initiating endothelial necroptosis. In contrast, melatonin treatment inhibited the Ripk3-PGAM5-CypD-mPTP cascade and thus reduced cellular necroptosis, conferring a protective advantage to the endothelial system in IR stress. These findings establish a new paradigm in microvascular IR injury and update the concept for cell death management handled by melatonin under the burden of reperfusion attack.

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“…Then, a luciferase-based ATP assay kit (Celltiter-Glo Luminescent Cell Viability assay; Promega, Madison, WI, USA; Catalog No. A22066) was used to analyze the ATP content according to the instructions [35]. ATP production was measured via a microplate reader (Epoch 2; BioTek Instruments, Inc.).…”

Section: Methodsmentioning

confidence: 99%

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

Feng¹,

Li²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The aim of our study is to investigate the molecular mechanism by which mammalian STE20-like kinase 1 (Mst1) participates in renal I/R injury through modifying mitophagy and the AMPK-YAP signalling pathway. Methods: WT mice and Mst1-knockout mice were subjected to renal ischaemia-reperfusion (I/R) in vivo. In vitro, the hypoxia-reoxygenation model was used with renal tubular epithelial cells to mimic renal I/R injury. Mitochondrial function was monitored via western blotting and immunofluorescence. Pathway blocker and siRNA knockout technology were used to establish the role of the AMPK-YAP signalling pathway in Mst1-mediated mitochondrial apoptosis in the setting of renal I/R injury. Results: Our data demonstrated that Mst1 expression was upregulated in response to renal I/R injury in vivo, and a higher Mst1 content was positively associated with renal dysfunction and more tubular epithelial cell apoptosis. However, genetic ablation of Mst1 improved renal function, alleviated reperfusion-mediated tubular epithelial cell apoptosis, and attenuated the vulnerability of kidney to I/R injury. In vitro, Mst1 upregulation induced mitochondrial damage including mitochondrial potential reduction, ROS overloading, cyt-c liberation and caspase-9 apoptotic pathway activation. At the molecular levels, I/R-mediated mitochondrial damage via repressing mitophagy and Mst1 suppressed mitophagy via inactivating AMPK signalling pathway and dowregulating OPA1 expression. Re-activation of AMPK-YAP-OPA1 signalling pathway provided a survival advantage for the tubular epithelial cell in the context of renal I/R injury by repressing mitochondrial fission. Conclusion: Overall, our results demonstrate that the pathogenesis of renal I/R injury is closely associated with an increase in Mst1 expression and the inactive AMPK-YAP-OPA1 signalling pathway. Based on this, strategies to repress Mst1 expression and activate mitophagy could serve as therapeutic targets to treat kidney ischaemia-reperfusion injury.

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Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms

Cited by 36 publications

References 48 publications

Sex differences influencing micro‐ and macrovascular endothelial phenotype in vitro

Sex differences influencing micro‐ and macrovascular endothelial phenotype in vitro

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

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