Celebrating Physiology in Cambridge, September 2026

From survival to disease: How fetal hypoxia reprogrammes the cardiovascular system

Chronic fetal hypoxia is a major challenge to fetal development, arising from placental insufficiency and underlying fetal growth restriction, which affects close to 10% of pregnancies worldwide. Understanding how the fetus adapts to oxygen deprivation is therefore fundamental to understanding survival before birth and cardiovascular health across the life course.

Our work overturned the prevailing view that the carotid body is inactive before birth, establishing its central role as the oxygen sensor initiating fetal cardiovascular defence to acute hypoxia. The carotid chemoreflex triggers peripheral vasoconstriction, redistributing blood flow towards vital organs – the fetal brain-sparing response. This vasoconstriction is sustained by hormones released into the fetal circulation and fine-tuned by our discovery of a local redox signalling pathway through interactions between nitric oxide and superoxide.

When fetal hypoxia becomes chronic, this defence is fundamentally reprogrammed. Carotid chemoreflex and sympathoadrenal responsiveness are attenuated, limiting the energetic cost of sustained neural activation, while control shifts towards local cardiovascular mechanisms. In the hypoxic fetus, peripheral vessels develop enhanced α-adrenergic responsiveness and a pro-constrictor redox phenotype, while cerebral vasodilator capacity and mechanisms supporting myocardial function are enhanced. These adaptations may help sustain redistribution of the fetal circulation during chronic hypoxia, but they come at a cost: the chronically hypoxic fetus has little additional cardiovascular reserve when acute hypoxia is superimposed. This provides a physiological explanation for the particular vulnerability of the growth-restricted fetus to acute stresses such as labour. Persistent hypoxia also transforms physiological redox signalling into oxidative stress. In the placenta, increased mitochondrial generation of reactive oxygen species quenches nitric oxide, reducing uteroplacental blood flow and fetal oxygen and nutrient delivery, thereby exacerbating fetal growth restriction.

Birth removes the chronic hypoxic stimulus, but the fetal cardiovascular legacy persists. We propose that the pro-constrictor phenotype that helped sustain fetal brain sparing becomes unmasked after birth as sympathetic vascular hyperreactivity and endothelial dysfunction, ultimately promoting hypertension in later life. Our latest work shows that maternal treatment of hypoxic pregnancy with the mitochondria-targeted antioxidant MitoQ protects placental function, restores perfusion, and prevents both fetal growth restriction and programmed hypertension in adult offspring. These findings establish mitochondria-derived oxidative stress as a causal mechanism linking chronic fetal hypoxia to cardiovascular disease in later life.

Thus, fetal hypoxia reveals a fundamental physiological continuum: from how the fetus senses and defends itself against oxygen deprivation, to how persistent fetal hypoxia transforms physiological adaptation into mechanisms that drive cardiovascular disease in later life.

STED microscopy and transmission electron microscopy reveal mitochondrial reverse remodelling following respiratory heart rate variability pacing in heart failure

Background: Respiratory heart rate variability (RespHRV) is a natural beat-to-beat variation in heart rate linked to respiration that is lost in heart failure. We have previously shown that restoring RespHRV using a novel biofeedback pacemaker improves cardiac function in an ovine model of heart failure with reduced ejection fraction (HFrEF). Recent proteomic and metabolomic analyses suggested improved mitochondrial function as a potential mechanism underlying this response. We therefore investigated whether RespHRV pacing restores mitochondrial structure in the failing heart.

Methods: Heart failure was induced in female Romney sheep by sequential coronary microembolisation. Animals were assigned to control (n=5), heart failure (HF; n=5), or heart failure treated with RespHRV pacing for two weeks (HF+R; n=5). Heart failure was induced in sheep by sequential coronary microembolization. Three months following heart failure induction, animals underwent instrumentation surgery and received two weeks of pacing therapy. Sheep were then euthanized, and cardiac tissue was collected for subsequent analyses. Surgical procedures, anaesthesia, and pharmacological protocols were performed as previously described by Shanks et al., (2022). Left ventricular tissue was analysed using stimulated emission depletion (STED) microscopy of TOMM20-labelled mitochondria and transmission electron microscopy (TEM) of mitochondrial ultrastructure. Proteomic and metabolomic analyses were used to provide mechanistic context. STED and TEM images were analysed using a linear mixed-effects model with group (C, HF, HF+R) as a fixed effect and animal included as a random intercept to account for clustering of myocytes within animals. Planned comparisons performed between groups used Least Significant Difference (LSD) tests. Data was expressed as mean and SEM.

Results: STED microscopy demonstrated a highly organised columnar arrangement of mitochondria in control myocardium that was disrupted in HF. Directionality analysis revealed loss of mitochondrial alignment in HF that was restored following RespHRV pacing (p=0.051). Quantification of TOMM20 labelling demonstrated a significant increase in TOMM20-positive area in HF+R compared with HF (p=0.005). TEM revealed marked disruption of mitochondrial cristae architecture in HF hearts, characterised by a significant reduction in cristae density compared with controls (p<0.001). Following two weeks of RespHRV pacing, cristae density was significantly increased compared with HF (p<0.001) and mitochondrial ultrastructure restored towards the control phenotype despite no change in total mitochondrial area fraction. Complementary proteomic analyses demonstrated restoration of mitochondrial proteins associated with oxidative metabolism and fatty acid β-oxidation, while paired plasma metabolomic analyses showed reductions in circulating long-chain acylcarnitines following pacing, consistent with improved mitochondrial oxidative function.

Conclusions: RespHRV pacing induces reverse remodelling of mitochondrial architecture in the failing heart. STED microscopy and TEM demonstrate restoration of mitochondrial organisation and cristae density, providing a structural basis for improved mitochondrial function. These findings identify mitochondrial recovery as a key component of the therapeutic response to RespHRV pacing and highlight the value of advanced imaging approaches for understanding mechanisms of cardiac repair.

High-altitude adaptation: Metabolic lessons from the mountains

High altitude presents a formidable physiological challenge: reduced oxygen availability (hypoxia) challenges cellular energy metabolism and redox homeostasis. Despite adaptive responses at the whole-body level that enhance convective oxygen delivery, tissue hypoxia persists, necessitating metabolic responses that alter oxygen utilisation. Notably, populations with a long history of residence at altitude have evolved distinctive physiological strategies that enable them to thrive in this environment. Understanding these adaptations can reveal fundamental principles governing human metabolism under conditions of limited oxygen availability.

This talk will explore how studies conducted during the Caudwell Xtreme Everest and Xtreme Everest 2 expeditions have shaped our understanding of metabolic responses to hypoxia. In lowlanders, exposure to high altitude induces extensive remodelling of skeletal-muscle metabolism and mitochondrial function. These responses may help preserve cellular energy homeostasis, but they are accompanied by reduced capacity for lipid oxidation and may contribute to the decline in physical performance seen during prolonged hypoxic exposure.

The Sherpa people provide an illuminating contrast. Their skeletal muscle exhibits a metabolic phenotype characterised by reduced reliance on fatty-acid oxidation, greater use of carbohydrate-derived substrates and efficient production of ATP relative to oxygen consumption. These characteristics are associated with genetic variation in pathways regulating cellular oxygen sensing and fuel selection, suggesting that natural selection has acted not simply on oxygen delivery, but also on the way oxygen is used.

I will also present recent work integrating metabolomic and genetic data across ascent to examine how ancestry, altitude and sex influence lipid metabolism and transport in Sherpas and lowlanders. Together, these studies highlight that metabolic adaptation—matching fuel selection and mitochondrial function to oxygen availability—is a central component of human adaptation to high altitude.

NeuroMap – Developing Cortical Mapping Techniques for Clinical Application in Neurological Disorders

Background

Transcranial Magnetic Stimulation (TMS) can quantify corticospinal tract function by extracting parameters from stimulus-response (recruitment) curves. Monitoring some of these parameters, such as slopes (k), maximum motor evoked potential (MEP) amplitudes (MEP_sat), and intensities at the steepest part of the slope (S₅₀), could help provide more individualised prognoses following neurological injury. However, current TMS protocols for generating recruitment curves are often restricted to measuring only one muscle at a time, via stimulation at the cortical hotspot corresponding to each muscle, making them time-consuming and clinically impractical. The aim of this study was to determine whether parameters derived for two muscles simultaneously from a single cortical location would be consistent, to provide evidence for optimised data acquisition times.

Methods

With ethical approval from the Imperial College Research Ethics Committee, thirteen healthy participants (7 male, 6 female; mean ± SD age: 26.54 ± 9.33 years, range 21-52 years) underwent neuronavigation-guided TMS of the motor cortex. Surface electromyography was recorded from the first dorsal interosseus (FDI) and triceps brachii (TRI) muscles. Recruitment curves were generated for both muscles at each hotspot and modelled with a four-parameter Boltzmann sigmoidal function (MEP_sat, EMG_base, S₅₀, k). Within-subject comparisons were carried out between on-hotspot and off-hotspot conditions using paired t-tests or Wilcoxon signed-rank tests. The relationship between Euclidean hotspot distance and the change in each parameter between stimulation conditions was assessed using Spearman’s correlation analysis. Significance was defined as p < 0.05.

Results

For FDI, off-hotspot stimulation increased median S₅₀ from 46.03% (IQR 43.94–60.71) to 72.84% (IQR 63.79–85.36) of maximum stimulator output (W = 87, p = 0.0007, r_c= 0.96), indicating that higher stimulus intensities were required to achieve equivalently sized responses. No significant effect was observed for the other FDI parameters (k: p = 0.84; MEP_sat: p = 0.50), indicating that off-hotspot FDI stimulation preserved the shape of recruitment curves. For TRI, no significant differences were observed between parameters derived from on- or off-hotspot stimulation (S₅₀: p = 0.62; k: p = 0.77; MEP_sat: p = 0.13).

Across participants, the change in FDI S₅₀ between stimulation conditions was positively correlated with the distance between FDI and TRI hotspots (r_s= 0.670, p = 0.015, 95% CI [0.172, 0.896]). No significant correlations were observed for any other FDI or TRI parameters.

Conclusion

Boltzmann recruitment curve parameters, particularly MEP_sat and k, were largely robust to some deviation from the optimal stimulation site, i.e. the hotspot. Although off-hotspot stimulation only increased FDI S₅₀, suggesting that muscle-specific variables such as differences in cortical representations may modulate the impact of spatial deviations, the overall preservation of Boltzmann parameters demonstrated that recruitment curves can be derived for two muscles simultaneously from a single cortical location. The findings of this study in healthy individuals support the feasibility of more efficient acquisition protocols and provide proof-of-concept for the assessment of multiple muscles at once. This represents an important first step towards clinically practical application, where rapid characterisation of corticospinal tract function could improve prognostication following neurological injury.

Sir Jospeh Barcroft 1872-1947 – pioneer of fetal and neonatal physiology

Joseph Barcroft was the third Professor of Physiology at the University of Cambridge and, during a prolific research career, pioneered the study of fetal and neonatal physiology. He was born in Ireland, to well-to-do parents and had a liberal upbringing grounded in Quaker principles. From an early age, his interests were in nature and science, not in poetic writing and reading literature. Initially taught by governesses, he attended non-conformist boarding schools strong in the sciences from age 12. During his last two school years, he enrolled at the University of London for a BSc degree awarded as he finished school. After a ‘recovery’ year, he matriculated at Kings College, Cambridge, in Natural Sciences, beginning a lifelong association with the College and the University. In 1897 he graduated with a first-class BA degree and began research in the Physiological Laboratory where he remained research active until his death 50 years later.

Barcroft was an experimental physiologist whose research had three main phases. First, he investigated saliva production, its oxygen requirement and neural regulation. He devised new techniques for measuring the oxygen content of small blood volumes and developed wider interests in tissue respiration, blood oxygen dissociation curves and pulmonary ventilation. In 1910, Barcroft was elected a Fellow of the Royal Society for his work in these areas. Next, he studied physiological adaptations to hypoxia by undertaking high-altitude expeditions and experimenting on himself in an air-tight glass chamber. The final phase of Barcroft’s research, for which he is best remembered now, began in the early 1930s. It sought to establish how fetuses thrived in conditions that Barcroft likened to Everest in utero. In acute experiments on anaesthetised pregnant sheep, he measured placental function, fetal growth rates, fetal haemoglobin and oxygen carrying capacity, fetal oxygen consumption, fetal respiratory movements, fetal and placental blood flow and changes in the circulation and lungs at the time of birth. Indeed, much of today’s diaspora of feto-placental and perinatal research can trace its origin back to the studies of Barcroft and his students and colleagues in Cambridge.

As a Quaker, Barcroft was seconded to Porton Down Experimental Station during both World Wars to oversee research on gas poisoning, for which he received the CBE. In 1925, he became the Chair of Physiology in Cambridge and began enlarging the Laboratory building and its staff. He chaired multiple committees, gave engaging undergraduate lectures and supervisions, and traveled widely to give lecture series and attend conferences abroad. After ‘retirement’, he became Director of a new ARC unit of Animal Physiology based in the Physiological Laboratory, with a remit to study ruminant metabolism. He supervised its activities alongside continuing his own perinatal research. He was knighted in 1935 and received numerous other honours and Honorary degrees. In total, Barcroft published three books and over 300 scientific papers and meeting proceedings. His epitaph was expressed most simply by Professor Adrian: “He was a very wise and kindly man as well as a great physiologist”.

Hodgkin and Huxley: giants of science.

Students of physiology or neuroscience will all recognise the names of Hodgkin and Huxley, particularly at Cambridge. Their achievements stand out as a high point in science.

Most will know about their experimental studies demonstrating how voltage-gated channels were involved in nerve impulses. Less widely recognised is their use of experimental data to develop a mathematical model explaining potential molecular mechanisms of impulses, and how influential this was. It’s very easy to forget that their work was undertaken with very basic electronics with semiconductors only being invented around the time they were working. Much of their equipment was hand-built, by themselves. There was very little information at the time about molecular structures or processes, the concept of a phospholipid bilayer cell membrane was only proposed a few years before they began working on squid giant axons. Data analysis depended upon hand-worked or hardware calculator-worked solutions without computers, yet they were using non-linear differential equations. A world war intervened in their research, taking them both away into military research, where their physics backgrounds enabled them to make substantial contributions, Hodgkin to the implementation of airborne microwave radar, Huxley to using radar to target anti-aircraft gunnery.

Hodgkin and Huxley also benefited from a very different academic world and research environment to today’s. Their work on giant squid required them being in Plymouth during the “squid season” (which took them away from undergraduate examinations). When their research resumed after the war they built their research case based on experimental studies done over a six year period before publishing the outcome as a series of 5 papers in the Journal of Physiology in 1952. This series of experiments culminated in the description of the voltage-dependent membrane conductances that underly the action potential. The papers combined description of application of a new scientific approach (voltage clamp) and identification of key properties of an underlying mechanism that must operate unseen at a molecular level. This was a huge achievement, deserving its description as groundbreaking. This was the impetus for their award of the Nobel Prize in 1963. Hodgkin and Huxley suggested that it “be regarded as a first approximation which needs to be refined and extended in many ways in the search for the actual mechanism”.

Both Hodgkin and Huxley went on to significant scientific achievements in their subsequent lives: Hodgkin moved on to work on the responses of photoreceptors to light, making a major contribution and Huxley moved to a chair at UCL, also moving field nerves to research on muscle force generation. where he developed the sliding filament hypothesis of striated muscle force generation. Both also took on major administrative and leadership roles, within universities, within the Royal Society and the Physiological Society. Both also became Masters of Trinity College Cambridge.

Hodgkin and Huxley were true giants of science of the order that rarely come along: they not only re-wrote the textbooks, they added an entirely new chapter.

PCOS-Like Follicular Arrest and Endocrine Disturbance Following Granulosa Loss of MRP4

Polycystic ovary syndrome (PCOS), characterized by a high androgen-to-estrogen ratio, follicular arrest and anovulation, is a reproductive and endocrine disorder affecting 10% of women of reproductive age worldwide ¹. Abnormalities in ovarian granulosa cells contribute to PCOS pathogenesis, although the underlying molecular mechanisms remain unclear. Previously, we demonstrated multi-drug resistance protein 4 (MRP4), a membrane protein of the ATP-binding cassette transporter subfamily C encoded by the human gene ABCC4, to be essential to uterine signaling pathways (i.e., prostaglandin E2 and Wnt/β-catenin) required for embryo implantation and female fertility². In the present study, we hypothesized that MRP4 might play a role in granulosa cells for ovarian functions.

We first examined MRP4 expression in mouse ovarian tissues and found its expression mainly in granulosa cells initiating at primary follicles and increasing gradually as follicles grow and peaking at late antral follicles. We next generated transgenic mouse models with granulosa-specific knockout of MRP4 by crossing MPR4-floxed (Abcc4^fl/fl) mice with Cyp19a1–Cre- or Amh-Cre-inserted one. Such conditional (granulosa-specific) knockout mice (cKO) were compared with Cre negative controls (Abcc4^fl/fl). Although these cKO mice were viable and grossly normal, they exhibited clear reproductive abnormalities in adulthood. Estrous cycle analysis showed a significantly (p <0.05) shortened estrus phase and prolonged diestrus/metestrus in cKO (n = 7 of Amh-Cre and n = 9 of Cyp19a1-Cre) in comparison to the controls (n = 12). Histological examination and follicle counting cross the entire ovary revealed a marked (p <0.05) accumulation of small follicles (primary and secondary) accompanied by a significant (p <0.05) reduction in large antral follicles in the cKO mice (n = 5 of Amh-Cre and n = 9 of Cyp19a1-Cre) versus those in controls (n = 12). In addition, cKO ovaries contained thin-walled oocyte-lacking follicular cysts, which was very rare (1 cyst in 12 ovaries) in the controls. Fertility testing over consecutive pregnancies demonstrated reduced reproductive capacity of the cKO (n = 5). Moreover, granulosa expression level of anti-Mullerian hormone (AMH) was significantly elevated in cKO ovaries, particularly in large follicles, which together suggested a PCOS-like follicular arrest phenotype in cKO mice. Consistently, spatial transcriptomic analysis of ovaries from the mice revealed a pathological granulosa cell transition in the cKO. The cluster of cells associated with steroidogenic function reduced in number, whereas a distinct population enriched in adhesion- and scaffold-related genes became predominant in cKO ovaries. Quantitative PCR analysis confirmed that primary granulosa cultures from MRP4 knockout mice exhibited downregulation of key steroidogenic markers, including Cyp11a1, Cyp19a1, and Fshr with impaired gonadotropin responsiveness. Mechanistically, intracellular cAMP- and Ca²⁺-overload was found in primary granulosa cells of MRP4 knockout, linking transporter loss to altered signaling homeostasis and granulosa dysfunction.

Taken together, these findings have revealed previously undefined role of MRP4 in regulating granulosa cell function and folliculogenesis. Deficiency of MPR4 triggers in a pathological transition of granulosa cells resulting in PCOS-like follicular arrest in mice, providing a novel mechanism for granulosa abnormalities in PCOS.

Maternal obesity programs adipogenic commitment in neonatal mesenchymal stem cells: a link to redox‐dependent FOXO1 signaling

Introduction: Maternal obesity increases the risk of obesity and metabolic disease in the offspring, however, the cellular mechanisms that program adipose tissue development remain poorly understood. Mesenchymal stem cells (MSCs), the precursors of adipocytes, may represent an early target of metabolic programming during fetal development. Previous studies have shown that MSCs isolated from neonates of mothers with obesity exhibit enhanced adipogenic differentiation potential (Iaffaldano et al. 2013; Chen et al. 2016).

Objective: This study investigated whether maternal obesity alters stemness, redox homeostasis and adipogenic commitment in neonatal MSCs from mothers with obesity compared to those from mothers with normal weight. We hypothesized that maternal obesity induces redox adaptations that could modulate Forkhead Box O1 (FOXO1) adipogenic pathway (Jing et al., 2007).

Methods: MSCs were isolated from Wharton’s jelly of umbilical cords from neonates born to mothers with normal weight (NW‐MSCs, n = 15) or obesity (OB‐ MSCs, n = 15). Basal MSCs were characterized for stemness properties and redox parameters. Cells were exposed to 250 μM hydrogen peroxide (H₂O₂) to assess antioxidant enzyme responses, and to measure intracellular levels of reactive oxygen species (ROS) and O2•‐ production in response to oxidative stress. Further, MSCs were subjected to adipogenic differentiation to evaluate FOXO1 expression and ROS responses. FOXO1 involvement was confirmed through acetyl‐FOXO1 localization, while adipogenesis was confirmed by Peroxisome Proliferator-Activated Receptor gamma (PPARγ) expression. All procedures were conducted according to the Helsinki Declaration and complied with all relevant institutional and national ethical regulations.

Results: Cells from both groups were positive for MSC markers CD73 and CD90, and CD105; and negative for CD11b, CD34, and CD45. Both NW‐MSCs and OB‐MSCs showed trilineage differentiation potential. OB‐MSCs exhibited reduced stemness characteristics, including lower octamer binding protein 3/4 (OCT3/4) expression and decreased clonogenic capacity (Figure 1, *p < 0.05 Mann−Whitney U test; **p < 0.01 Tukey’s range post hoc test, n = 6 NW‐MSCs and 6 OB‐MSCs). These cells also displayed increased mitochondrial superoxide levels and reduced superoxide dismutase 2 (SOD2) expression, indicating mitochondrial oxidative stress. In addition, OB‐MSCs showed increased GSH levels, compared to NW‐MSCs, suggesting an adaptive redox response (Figure 2, *p < 0.05, Mann−Whitney U test, median ± range, n = 9 NW‐MSCs and 7 OB‐MSCs). During early adipogenic commitment, OB‐MSCs exhibited higher FOXO1 expression levels, and predominant cytoplasmatic localization during early adipogenesis, consistent with reduced repression of the adipogenic regulator PPARγ. Furthermore, adipocytes derived from OB‐MSC displayed increased PPARγ expression at later stages of differentiation (Figure 3, ^#p < 0.05 Paired Wilcoxon signed‐rank test compared to Day 0; *p < 0.05 and ***p < 0.0001Tukey’s range post hoc test, n = 6 NW‐MSCs and 6 OB‐MSCs).

Conclusions: Maternal obesity impacts stemness, redox balance, and FOXO1 dynamics in neonatal MSCs, leading to dysregulated FOXO1 compared to NW‐MSCs. These findings support a model in which maternal obesity induces mitochondrial oxidative stress in neonatal MSCs, disrupting FOXO1 regulation, thereby shifting early adipogenic signaling toward enhanced adipocyte commitment. This mechanism may expand the adipocyte precursor pool, potentially predisposing the progeny to metabolic disorders later in life (Bellalta et al. 2026).

Waveform-derived length and time constants for propagating action potentials

Introduction. For more than a century, cable theory has provided the mathematical language for understanding voltage spread in neurons. By the 1950s, the responses to subthreshold stimuli were largely established, permitting the expression of passive cable properties in terms of intuitive and experimentally-measurable length and time constants. In Cambridge, Hodgkin and Huxley then provided a quantitative description¹ of the non-linear ionic currents that generate and propagate the action potential (AP). Their active cable equation powerfully relates conduction velocity to cable properties and waveform shape, but has resisted reduction to measurable descriptors analogous to the passive length and time constants.

Aim.

We sought to extend the quantitative framework of Hodgkin, Huxley, Rushton and others² by defining length and time constants of AP propagation and establishing their relationships with conduction velocity and cable properties.

Method
We analysed propagating APs in a computational cable model^3,4 of an unmyelinated axon with Hodgkin-Huxley ion channel kinetics. We identified specific instants during AP propagation at which net transmembrane ionic current is transiently zero, while axial and capacitive currents remain non-zero. At these Transmembrane Current Transition (TCT) points, the active cable equation simplifies, allowing us to relate propagation velocity only to the curvature of the action potential upstroke, axial resistance and membrane capacitance.

Results

At the TCTs, we defined a waveform curvature parameter, kappa, as the ratio of the acceleration to the rate of change of membrane potential. From this, we defined and derived length and time constants for the propagating AP. Measured values of AP propagation velocity (Fig 1A), AP wavefront length constant (1B) and AP upstroke time constant (Fig 1C) were shown to be equal to those calculated from kappa (Fig 1D). Our simulations show that kappa is determined by ion channel properties and membrane capacitance but not axial resistance, explaining why fibre diameter scales velocity without altering action potential shape. We suggest single-electrode methods for the experimental measurement of kappa: from the exponential rise of the upstroke with time (Fig 1C), and from the initial slope of an action-potential phase plot (not shown). Thus, kappa provides a single-value descriptor of AP shape that provides the missing bridge between the measurable waveform and physiological measures of propagation. We further show that kappa is the local real Laplace exponent of the AP upstroke, and thereby provides a framework to extend this approach into other physiologically realistic geometries, including myelinated, tapering and terminated cables.

Conclusions
By exploiting TCT points at which the active cable equation simplifies, we extend the elegant analytical framework of cable constants from passive to active membranes. We show that exact, measurable AP length and time constants are derivable from waveform recordings and establish a natural foundation for extension to myelinated axons and complex geometries.

1. Hodgkin AL & Huxley, AF J Physiol (1952) 117, 500–44.

2. Jack J, et al (OUP: 1975).

3. Fraser JA & Huang CL (2007) Prog Biophys Mol Biol 94, 336–72.

4. Fraser JA & Huang CL (2004) J Physiol 559, 459–478.

PAK1/2 signalling and therapeutic activation in cardiac protection

PAK1/2 Signalling and Therapeutic Activation in Cardiac Protection

Yu He¹, James SH Bae¹ and Ming Lei¹

¹Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom

Corresponding to: Ming Lei (ming.lei@pharm.ox.ac.uk)

Over the past decade, work from our laboratories and others has established p21-activated kinases 1 and 2 (PAK1/2) as important regulators of cardiac homeostasis and potential therapeutic targets in cardiovascular disease. We have demonstrated that PAK1 plays a critical role in regulating ion channels, maintaining intracellular Ca²⁺ homeostasis and electrophysiological stability in the heart^1-6. Furthermore, activation of PAK1 signalling exerts cardioprotective effects against pathological hypertrophy, fibrosis, and ischaemia–reperfusion injury and heart failure ^1-7. More recently, we and others found that PAK2 is abundantly localised in close proximity to the endoplasmic reticulum (ER) membrane, where it acts as a key regulator of the IRE1/XBP1-dependent unfolded protein response (UPR), providing an additional mechanism of cardioprotection during cellular stress^{8, 9}.

Building on these mechanistic insights into PAK1/2-mediated cardioprotection, we have developed a novel peptide-guided strategy for discovery kinase activators. By identifying and targeting a previously unrecognised autoinhibitory interface between the PAK1/2 kinase domain (KD) and autoinhibitory domain (AID), we demonstrated that rational modulation of kinase autoinhibition can enhance PAK1/2 activity¹⁰. This approach has enabled the development of a series of potent small-molecule PAK1/2 activators and may provide a broadly applicable strategy for therapeutic kinase activator discovery—an area that remains substantially less explored. Importantly, these PAK1/2 activators exert robust antihypertrophic effects, attenuating cardiomyocyte hypertrophy and improving pathological myocardial remodelling¹⁰.

Collectively, our studies and those of others identify PAK1/2 as central regulators of Ca²⁺ homeostasis, electrophysiological stability, ER stress responses, and myocardial remodelling, supporting their development as novel therapeutic targets for cardiac hypertrophy, heart failure, and arrhythmias. By restoring Ca²⁺ homeostasis and modifying the arrhythmogenic substrate, pharmacological activation of PAK1/2 may offer a complementary therapeutic strategy to existing antiarrhythmic treatments. Further elucidation of the cellular and molecular mechanisms linking PAK1/2 activation to antihypertrophic and antiarrhythmic effects will be important for optimising these compounds and advancing PAK1/2-targeted therapies toward clinical translation.

Registration opens	04 June 2026
Abstract submission opens	18 May 2026
Abstract submission closes	3 July 2026
Conference Attendance Award deadline	30 June 2026
Registration deadline	03 September 2026
Meeting date	17-18 September 2026

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Celebrating Physiology in Cambridge

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13:40 SA01 From survival to disease: How fetal hypoxia reprogrammes the cardiovascular system

14:05 SA02 Structured hybrid exercise restores cardiac function in murine cardiometabolic HFpEF

14:30 C01 STED microscopy and transmission electron microscopy reveal mitochondrial reverse remodelling following respiratory heart rate variability pacing in heart failure

14:40 SA03 High-altitude adaptation: Metabolic lessons from the mountains

15:10 SA04 Cortical and collicular contributions to visual spatial detection in freely moving mice

15:35 SA05 Hunting down the neural pulse generators controlling fertility

16:00 C02 NeuroMap: Developing cortical mapping techniques for clinical application in neurological disorders

16:35 SA06 From Foster to the future: Physiology practical class teaching in Cambridge

17:00 PL07 Sir Jospeh Barcroft 1872-1947: Pioneer of fetal and neonatal physiology

17:25 PL06 Hodgkin and Huxley: Giants of science

09:00 SA07 How to build the human lungs

09:25 The remarkable placenta: Shaping maternal and offspring metabolic health

09:50 C03 PCOS-like follicular arrest and endocrine disturbance following granulosa loss of MRP4

10:00 SA08 Genomic imprinting as a regulator of postnatal physiology

11:00 SA09 Insights into endocrine and metabolic phenotypes from humans carrying rare genetic variants

13:15 Origins of obesity: Impact of obesity in pregnancy on the offspring hypothalamus

13:40 SA10 Using ‘omics analyses to generate new insights into adipocyte metabolism

14:05 C04 Maternal obesity programs adipogenic commitment in neonatal mesenchymal stem cells: A link to redox‐dependent FOXO1 signaling

14:15 SA11 Unravelling obesity biology through natural genetic variation in dogs

15:00 The Hodgkin and Huxley legacy: A personal appreciation

15:10 C05 Waveform-derived length and time constants for propagating action potentials

15:20 From the physiology department to the clinic: Electrophysiology research in a clinical setting

15:50 PL08 PAK1/2 signalling and therapeutic activation in cardiac protection

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