Biology subjects

Mackay, C.

Publications and source records attributed to Mackay, C..

5 recordsLinked to original sources

bioRxiv2026

Wnts are endothelial cell-derived PKD1/PKD2-dependent autocrine/paracrine vasodilators

BackgroundWingless/Int-1 (Wnts) proteins are canonical Frizzled receptor ligands. Recent evidence indicates that some Wnts, including Wnt9b and Wnt5a, bind to polycystin 1 (PKD1), a transmembrane protein which can couple to polycystin 2 (PKD2) to form a non-selective cation channel. The functional significance of Wnts binding to PKD1 is unclear. Here, we tested the hypothesis that Wnts act through PKD1/PKD2 channels on endothelial cells (ECs) to regulate arterial contractility and blood pressure and investigated the cellular source and secretory regulation of vasoactive Wnt proteins. MethodsA wide variety of approaches, including inducible EC-specific PKD1 and PKD2 knockout mice, reverse-transcription polymerase chain reaction, Western blotting, immunofluorescence, pressurized artery myography, blood pressure measurements, patch-clamp electrophysiology, in vivo and in vitro Wnt and nitric oxide assays, and Wnt secretion assays. ResultsIntravascular Wnt9b or Wnt5a administration stimulates an EC PKD1/PKD2-dependent dilation in pressurized resistance-size arteries. Wnt9b and Wnt5a are present in serum and plasma and intravenous infusion rapidly stimulates a blood pressure reduction which requires EC PKD1. Wnts stimulate a PKD1-dependent non-selective cation current in ECs which through Ca2+ signaling activates endothelial nitric oxide synthase (eNOS) and small conductance Ca2+-activated K+ channels to induce vasodilation. Wnt9b acts solely via PKD1/PKD2 channels, whereas Wnt5a stimulates signaling through PKD1/PKD2, Frizzled-7 (Fzd-7), Dishevelled and c-Jun N-terminal kinase (JNK). Intravascular flow stimulates angiotensin II type 1 (AT1) receptors, which through Gq/11 and Porcupine activate Wnt9b and Wnt5a secretion in ECs. Wnts secreted in response to flow activate PKD1/PKD2 signaling in ECs and contribute to flow-mediated vasodilation. ConclusionsIntravascular flow activates AT1 receptors, which through Gq/11 and Porcupine stimulate Wnt9b and Wnt5a secretion in ECs. Wnt9b activates PKD1/PKD2 channels whereas Wnt5a stimulates both PKD1/PKD2 and Fzd-7 in ECs to induce vasodilation. Wnts contribute to flow-mediated autocrine/paracrine dilation and reduce blood pressure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/712518v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1fa876aorg.highwire.dtl.DTLVardef@d05bd5org.highwire.dtl.DTLVardef@13d276corg.highwire.dtl.DTLVardef@1e75b7b_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Pharmacological inhibition of mitochondrial fission mitigates experimental thoracic aortic aneurysm

Thoracic aortic aneurysm (TAA) is increasingly recognized as a vascular degenerative disease and is typically diagnosed incidentally due to its asymptomatic nature. TAA is clinically associated with the dilation of the aorta and excessive vascular remodeling, which can lead to aortic rupture if left untreated. Angiotensin II (Ang II), an active peptide in the renin-angiotensin system, has been widely implicated in the development of TAA. The current study investigated the role of mitochondrial dynamics in the onset and progression of TAA. Male ApoEKO mice (8-10 weeks old) were infused with Ang II (1.44 mg/kg/day) and treated with mitochondrial division inhibitor 1 (mdivi-1) at a dose of 0.12 mg/kg/day. After 4 weeks of Ang II infusion, the ApoEKO mice developed TAA. Excessive mitochondrial fission was observed in thoracic vascular smooth muscle cells (vSMCs) using transmission electron microscopy (TEM) and confocal microscopy in response to angiotensin II (Ang II) treatment, which was reduced by mdivi-1. Echocardiographic and histological analyses of the Ang II-infused thoracic aorta revealed increased aortic dilation, vascular remodeling, and perivascular fibrosis. Pathological changes associated with Ang II-induced TAA were mitigated by mdivi-1. Co-treatment of isolated adult murine thoracic aortic vSMCs with mdivi-1 resulted in decreased mitochondrial fission, hyperproliferation, and phenotypic switching, accompanied by improved mitochondrial metabolism. Treatment with mdivi-1 inhibited Ang II-induced NF-{kappa}B signaling in vSMCs by blocking the nuclear translocation of p65 and cell cycle markers, thereby limiting inflammation and hyperproliferation. In conclusion, the inhibition of mitochondrial fission reduced pathological changes by mitigating vascular remodeling, vSMC hyperproliferation, and vSMC phenotypic switching associated with Ang II-induced TAA. The clinical utility of inhibiting mitochondrial fission warrants further investigation, which may lead to a novel therapeutic strategy for preventing TAA development.

physiology↗

bioRxiv2021

The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice

Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. We have previously demonstrated that a subset of spinal V3 neurons contributes to stable locomotion by mediating mutual excitation between left and right lumbar rhythm generators (RGs). Here, we expanded our investigation to the V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used lateral-sequence walk. To understand the functional roles of V3 aLPNs, we adapted our previous model of spinal circuitry controlling quadrupedal locomotion (Danner et al., 2017), by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The updated model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left-right interactions within lumbar and cervical cords, promote left-right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.

neuroscience↗

bioRxiv2021

Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma

Interleukin-13 (IL-13) and other Th2 cytokines are important regulators of airway hyper-responsiveness, immune cell infiltration and inflammation in allergic asthma, and are produced when immune cells, such as type 2 innate lymphoid cells (ILC2s) and mast cells, are stimulated with IL-33. Here, we report that the IL-33-dependent secretion of IL-13 from ILC2s is prevented by inhibition of the salt-inducible kinases (SIKs), as we have shown previously in mast cells (Darling NJ et al., 2021, J. Biol. Chem. doi: 10.1016/j.jbc.2021.100428). We also report that a new SIK inhibitor with improved pharmacokinetic properties suppresses the recruitment of eosinophils to the lungs and serum immunoglobulin E (IgE) levels in the Alternaria alternata-induced model of allergic asthma. Our results suggest that drugs targeting SIK isoforms may have therapeutic potential for the treatment of asthma.

immunology↗

bioRxiv2017

Improving data availability for brain image biobanking in healthy subjects: practice-based suggestions from an international multidisciplinary working group

Brain imaging is now ubiquitous in clinical practice and research. The case for bringing together large amounts of image data from well-characterised healthy subjects and those with a range of common brain diseases across the life course is now compelling. This report follows a meeting of international experts from multiple disciplines, all interested in brain image biobanking. The meeting included neuroimaging experts (clinical and non-clinical), computer scientists, epidemiologists, clinicians, ethicists, and lawyers involved in creating brain image banks. The meeting followed a structured format to discuss current and emerging brain image banks; applications such as atlases; conceptual and statistical problems (e.g. defining normality); legal, ethical and technological issues (e.g. consents, potential for data linkage, data security, harmonisation, data storage and enabling of research data sharing). We summarise the lessons learned from the experiences of a wide range of individual image banks, and provide practical recommendations to enhance creation, use and reuse of neuroimaging data. Our aim is to maximise the benefit of the image data, provided voluntarily by research participants and funded by many organisations, for human health. Our ultimate vision is of a federated network of brain image biobanks accessible for large studies of brain structure and function.

neuroscience↗