Purinergic receptor stimulation induces calcium oscillations and smooth muscle contraction in small pulmonary veins

Henríquez, Mauricio; Fonseca, Marcelo; Perez‐Zoghbi, Jose F.

doi:10.1113/jp274731

Cited by 15 publications

(9 citation statements)

References 69 publications

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“…Excitation–contraction coupling in TPCs is poorly described. Our results strongly suggest that a combination of P2X (isoforms 2 and/or 4) receptor-dependent Ca 2+ influx and P2Y (likely isoform 2) receptor-activated phospholipase C β -dependent Ca 2+ release from the sarcoplasmic reticulum – the latter being critical and resembling the recently reported mechanism of vascular smooth muscle cell contraction in small pulmonary veins ( Henriquez et al, 2018 ) – provides the [Ca 2+ ] c elevation required for force generation ( Berridge, 2008 ). P2X and P2Y receptors act on different time scales and display different ligand sensitivity, with EC 50 values in the nanomolar (P2Y) vs. micromolar (P2X) range ( North, 2002 ).…”

Section: Discussionsupporting

confidence: 77%

ATP activation of peritubular cells drives testicular sperm transport

Fleck

Kenzler

Mundt

et al. 2021

eLife

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Spermatogenesis, the complex process of male germ cell proliferation, differentiation, and maturation, is the basis of male fertility. In the seminiferous tubules of the testes, spermatozoa are constantly generated from spermatogonial stem cells through a stereotyped sequence of mitotic and meiotic divisions. The basic physiological principles, however, that control both maturation and luminal transport of the still immotile spermatozoa within the seminiferous tubules remain poorly, if at all, defined. Here, we show that coordinated contractions of smooth muscle-like testicular peritubular cells provide the propulsive force for luminal sperm transport toward the rete testis. Using a mouse model for in vivo imaging, we describe and quantify spontaneous tubular contractions and show a causal relationship between peritubular Ca2+ waves and peristaltic transport. Moreover, we identify P2 receptor-dependent purinergic signaling pathways as physiological triggers of tubular contractions both in vitro and in vivo. When challenged with extracellular ATP, transport of luminal content inside the seminiferous tubules displays stage-dependent directionality. We thus suggest that paracrine purinergic signaling coordinates peristaltic recurrent contractions of the mouse seminiferous tubules to propel immotile spermatozoa to the rete testis.

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Section: Discussionsupporting

confidence: 77%

ATP activation of peritubular cells drives testicular sperm transport

Fleck

Kenzler

Mundt

et al. 2021

eLife

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“…Consistent with this, knocking out P2Y 2 receptors had no effect on UTP-evoked contractions of mouse coronary arteries [ 60 ]. Interestingly, a tenfold higher concentration of AR-C118925XX virtually abolished contractions of rat small pulmonary veins induced by ATP [ 75 ]. The inactivity of AR-C118925XX in the rIPA is unlikely to be because the concentration used was too low, as it did inhibit UTP-evoked vasodilation.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of P2Y receptor subtypes mediating vasodilation and vasoconstriction of rat pulmonary artery using selective antagonists

Dales

Mitchell

Gurney

et al. 2022

Purinergic Signalling

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Pulmonary vascular tone is modulated by nucleotides, but which P2 receptors mediate these actions is largely unclear. The aim of this study, therefore, was to use subtype-selective antagonists to determine the roles of individual P2Y receptor subtypes in nucleotide-evoked pulmonary vasodilation and vasoconstriction. Isometric tension was recorded from rat intrapulmonary artery rings (i.d. 200–500 µm) mounted on a wire myograph. Nucleotides evoked concentration- and endothelium-dependent vasodilation of precontracted tissues, but the concentration–response curves were shallow and did not reach a plateau. The selective P2Y2 antagonist, AR-C118925XX, inhibited uridine 5′-triphosphate (UTP)- but not adenosine 5′-triphosphate (ATP)-evoked relaxation, whereas the P2Y6 receptor antagonist, MRS2578, had no effect on UTP but inhibited relaxation elicited by uridine 5′-diphosphate (UDP). ATP-evoked relaxations were unaffected by the P2Y1 receptor antagonist, MRS2179, which substantially inhibited responses to adenosine 5′-diphosphate (ADP), and by the P2Y12/13 receptor antagonist, cangrelor, which potentiated responses to ADP. Both agonists were unaffected by CGS1593, an adenosine receptor antagonist. Finally, AR-C118925XX had no effect on vasoconstriction elicited by UTP or ATP at resting tone, although P2Y2 receptor mRNA was extracted from endothelium-denuded tissues using reverse transcription polymerase chain reaction with specific oligonucleotide primers. In conclusion, UTP elicits pulmonary vasodilation via P2Y2 receptors, whereas UDP acts at P2Y6 and ADP at P2Y1 receptors, respectively. How ATP induces vasodilation is unclear, but it does not involve P2Y1, P2Y2, P2Y12, P2Y13, or adenosine receptors. UTP- and ATP-evoked vasoconstriction was not mediated by P2Y2 receptors. Thus, this study advances our understanding of how nucleotides modulate pulmonary vascular tone.

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“…Immunohistochemical signals for CD3, CD68, caspase 3, and Ki67 were quantified using the AdipoGauge software package (83). The thickness of the tunica media and vessel diameter were measured as described previously by Henriquez, et al (84). Briefly, manually outlined segmentation was performed for the external and internal perimeter of the H&E-stained pulmonary vessels from mouse lung sections.…”

Section: Histopathology Analysesmentioning

confidence: 99%

Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension

et al. 2022

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People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.

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Purinergic receptor stimulation induces calcium oscillations and smooth muscle contraction in small pulmonary veins

Cited by 15 publications

References 69 publications

ATP activation of peritubular cells drives testicular sperm transport

ATP activation of peritubular cells drives testicular sperm transport

Characterisation of P2Y receptor subtypes mediating vasodilation and vasoconstriction of rat pulmonary artery using selective antagonists

Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension

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