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Published in final edited form as: J Vasc Res. 2024 Dec 11;62(2):78–87. doi: 10.1159/000543116

Functional adaptations in coronary reactivity following healthy pregnancy in swine

Selina M Tucker 1, Salman I Essajee 1, Cooper M Warne 1, Gregory M Dick 1, Styliani Goulopoulou 2, Johnathan D Tune 1
PMCID: PMC11961330  NIHMSID: NIHMS2042154  PMID: 39662079

Abstract

Introduction:

This study was designed to test the hypothesis that coronary artery adaptations during the postpartum period are related to underlying reductions in endothelium-dependent relaxation and/or augmented smooth muscle vasoconstrictor responsiveness.

Methods:

In vivo experiments were performed in control (nonpregnant) and postpartum swine 35–45 days post-delivery, with isometric tension experiments performed in isolated coronary arteries from those animals.

Results:

Coronary artery rings demonstrated increases in active tension generation following incremental increases in passive stretch with no differences between groups. Endothelium-dependent relaxation to bradykinin was attenuated in arteries from postpartum swine vs. control (P < 0.005). Concentration-dependent contractions to the thromboxane A2 mimetic U46619 (0.1 nM – 1 μM) were shifted rightward (EC50 27 ± 10 nM vs. 238 ± 66 nM; P < 0.01) in arteries from postpartum swine, with no changes in maximum contractile responses (P = 0.68). Intracoronary administration of U46619 (1 nM – 1 μM) in open-chest swine decreased coronary blood flow ~45 ± 3% in nonpregnant controls but had no effect on coronary blood flow in postpartum swine. Concentration-dependent contractions to KCl (5 – 90 mM) showed a rightward shift in arteries from postpartum swine (15.6 ± 1.4 mM vs. 21.8 ± 1.9 mM; P = 0.03), with no change in maximum response. Taken together, the postpartum period is associated with reduced endothelium-dependent relaxation and responsiveness to receptor-dependent and independent vasoconstrictor stimuli.

Conclusion:

These findings indicate that chronic exposure of the coronary circulation to the pregnancy/postpartum milieu results in functional adaptations in sensitivity to paracrine/hormonal compounds that should be further explored.

Keywords: Postpartum, coronary circulation, thromboxane A2

INTRODUCTION

Recent estimates from the World Health Organization project that a woman dies every two minutes from a pregnancy or childbirth-related complication [1]. Understanding of the etiologies responsible for these maternal deaths remains poor. An especially vulnerable phase is the postpartum period, where ~53% of all deaths occur between 7 days to 1 year after delivery [2]. Cardiovascular disease is the leading cause of maternal mortality during this period, accounting for over 33% of related deaths [3]. Such casualties are typically attributed to hormonal, metabolic, and hemodynamic “stress test” on the maternal system [4, 5]. Presently, there is limited understanding of the molecular pathways/mechanisms responsible for the increased incidence of cardiovascular complications during the postpartum period.

Emerging evidence indicates that adverse cardiovascular outcomes in the postpartum period could be related, at least in part, to structural and functional adaptations in the coronary circulation. This hypothesis is supported by Hoonigberg et al. who found reductions in coronary flow reserve (CFR) in postpartum women (≤ 1 month following delivery) following either healthy or complicated pregnancies [6]. Recent data from our laboratory are consistent with this finding and support that the balance between coronary blood flow and myocardial metabolism is impaired at rest and during catecholamine-mediated increases in myocardial oxygen consumption (MVO2) in swine during the postpartum period [7]. Augmented coronary vascular resistance in postpartum swine was also associated with myocardial capillary rarefaction [7]. These initial findings are consistent with an elevated risk of ischemic heart disease during the postpartum period [8] and highlight the crucial need for further investigation.

The purpose of this study was to test the hypothesis that coronary adaptations during the postpartum period after a healthy pregnancy are related to reductions in endothelium-dependent relaxation and/or augmented smooth muscle vasoconstrictor responsiveness. This hypothesis was examined by isometric tension studies on coronary arteries isolated from control (nonpregnant) and postpartum swine during the puerperium period (35–45 days post-delivery). Based on prior evidence of postpartum alterations in vascular reactivity to potassium chloride (KCl), acetylcholine, and thromboxane A2 [9–11], we examined concentration-dependent coronary artery responses to smooth muscle depolarization to KCl (5 – 90 mM), the endothelium-dependent vasodilator bradykinin (1 nM – 1 μM) and the cyclooxygenase-derived vasoconstrictor thromboxane A2 (1 nM – 1 μM). In vivo coronary blood flow responses to intracoronary thromboxane A2 (1 nM – 1 μM) were also measured in open-chest anesthetized swine. Data from these experiments provide novel insight into functional adaptations in the coronary circulation following a healthy pregnancy.

MATERIALS AND METHODS

Swine and in vivo preparation

Comprehensive description of phenotypic variables for each group was previously published by our group [7]. All animals were housed with access to water and enrichment continuously and fed standard chow twice daily as recommended by breeder. Domestic (Yorkshire) control (non-pregnant; n = 11, 200–215 kg) and postpartum swine (35–45 days post-delivery; n = 5, 60–65 kg) were sedated with Telazol (5 mg/kg), xylazine (2.5 mg/kg), and ketamine (2.5 mg/kg, im) prior to anesthesia with buprenorphine (0.03 mg/kg, im) and alpha-chloralose (60 mg/kg, iv). Only female swine were used in this study as the postpartum period is a uniquely female condition following pregnancy. Postpartum swine produced only one litter (average size 14 ± 3). All postpartum swine lactated and weaned piglets at 28 days post-delivery. No cycling or fertility issues were observed by the breeder (Oakhill Genetics, IL).

Anesthetized swine were intubated and ventilated with O2-supplemented room air to achieve > 95% oxyhemoglobin saturation and an end tidal CO2 of ~ 40 mmHg as measured by aural pulse oximetry and inline capnography, respectively. Bilateral femoral cut downs were performed, and catheters were placed in both femoral arteries and one femoral vein. One femoral artery catheter provided continuous measurement of systemic blood pressure and heart rate, while the venous catheter allowed for administration of drugs (supplemental α-chloralose, heparin). The second femoral artery catheter was placed in a subset of control (n = 3) and postpartum (n = 2) swine and used to supply blood to an extracorporeal servo-controlled pump to perfuse the left anterior descending (LAD) coronary artery at a constant designated pressure as previously described by our laboratory [12]. Systemic hemodynamic and coronary responses to intravenous dobutamine (1 – 30 μg/kg/min) were performed in control (n = 10) and postpartum (n = 5) swine as part of a previously published investigation [7]. Following completion of experiments, animals were euthanized by electrical fibrillation and the heart excised.

Isometric tension studies

Hearts from control (n = 11) and postpartum (n = 5) swine were excised and submerged in cold (4°C) normal saline. Left circumflex coronary arteries were isolated, cut into ~3-mm rings, and mounted in water-jacketed organ baths (37°C) filled with Krebs solution containing (in mM) 118 NaCl, 5 KCl, 2.5 CaCl2, 1.2 NaH2PO4, 1.2 MgSO4, 25 NaHCO3, and 10 glucose. Repeated 5 min contractions with 60 mM KCl at successively greater internal circumferences determined the optimal passive tension required for maximal coronary artery contraction. Passive tension was increased in 1 g increments until K+-mediated increases in artery tension changed less than 20% as we have shown previously [13]. Once optimal loading conditions were determined, arteries were subjected to a KCl dose-response curve (5 – 90 mM), washed, and allowed to return to baseline tension. Select arteries were incubated with vehicle (ethanol 0.1%) or the thromboxane A2 antagonist S18886 (0.1 nM; Tocris Bioscience, Minneapolis, MN) for 15 min followed by a dose-response study to the thromboxane A2 mimetic U46619 (0.1 nM – 1 μM; Tocris Bioscience). Coronary artery responses to the endothelium-dependent vasodilator bradykinin (1 nM – 1 μM; Tocris Bioscience) were determined on stable U46619 contractions. Effects of the L-type Ca2+ channel antagonist diltiazem (1 nM – 100 μM) on U46619-mediated coronary contractions were also assessed in control arteries (n = 8).

In vivo coronary response to U46619

The LAD coronary artery was cannulated, and coronary pressure maintained at 100 mmHg by a servo-controlled roller pump system in control (n = 3) and postpartum (n = 2) swine as previously described by our laboratory [12]. Following a ~15 min stabilization period, bolus intracoronary infusions of U46619 were administered in a concentration-dependent manner (to reach coronary concentrations of 10 nM – 1 μM). Lowest values of coronary blood flow were recorded following each infusion and coronary flow allowed to stabilize for ~3 min between each dose.

Statistical analyses

Statistical analyses were performed in GraphPad Prism (version 10) and Sigma Plot (version 14.0), and comparisons were made using unpaired t-test or two-way analysis of variance (ANOVA) (Factor A: Group; Factor B: Dose) as appropriate. When significance was found with ANOVA, a Student-Newman-Keuls test was performed to identify differences between groups and/or dose levels accounting for multiple comparisons. All values are presented as mean ± SEM. For all statistical comparisons, P < 0.05 was considered statistically significant.

RESULTS

Length and endothelial-dependent characteristics

The passive tension for optimal contraction of isolated coronary arteries from control (n = 11) and postpartum (n = 5) swine was determined by incremental increases in circumferential stretch and active contraction stimulated by 60 mM KCl. No differences in active-passive tension relationships were observed between groups (Fig. 1A), as quantified by calculations of the area under the curve (Control: 1423 ± 40 vs. Postpartum: 1419 ± 29; P = 0.94), maximum active tension (Control: 91.4 ± 4.8 vs. Postpartum: 88.6 ± 3.9 mN; P = 0.68), or passive tension at optimal length (Control: 28.0 ± 1.3 vs. Postpartum: 27.2 ± 1.2 mN; P = 0.70). Endothelium-dependent relaxation to bradykinin was significantly attenuated in coronary arteries from postpartum swine at concentrations ranging from 10 nM to 1 μM (Fig. 1B; P < 0.005). Maximal coronary relaxation to 1 μM bradykinin averaged 71 ± 5% in control (n = 5) vs. 54 ± 3% in postpartum (n = 4) arteries. A significant rightward shift in endothelium-dependent relaxation was observed, as the EC50 increased from 5 ± 3 nM in control arteries to 501 ± 408 nM in arteries from postpartum swine (Fig. 1C, P < 0.005).

Figure 1.

Figure 1.

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A) Active-passive tension relationship of all coronary arteries used for reactivity studies (Control; n = 11, Postpartum; n= 5). B) Bradykinin dose-response relaxation in control (closed circles; n = 5) and postpartum (open circles; n = 4) coronary arteries. C) LogEC50 of bradykinin-mediated relaxation. A, B) Two-way ANOVA with Student-Newman-Keul post-hoc test. C) Student t-test. *P < 0.05 vs. Control.

Thromboxane A2-induced coronary artery contraction

Coronary responses to thromboxane A2 were assessed by dose-response studies to the thromboxane mimetic U46619 (1nM to 1μM). U46619-induced contractions were attenuated in postpartum arteries at 10 – 100 nM (Fig. 2A; P < 0.05), and the EC50 was shifted significantly rightward from 27 ± 10 nM in control arteries (n = 6) to 238 ± 66 nM in arteries from postpartum swine (n = 5) (Fig. 2B, P = 0.008). However, maximum contractions to 1μM U46619 were not different between groups (Control: 106 ± 8 mN vs. Postpartum: 112 ± 20 mN; P = 0.77). Validation studies demonstrated that the L-type calcium channel blocker diltiazem produced concentration-dependent reductions in U46619 contractions up to 88 ± 2% in nonpregnant swine (Fig. 2C; n = 8). Maximum contractions in control arteries with incubation of vehicle or S18886 (Fig. 2D; P < 0.01) and in postpartum arteries with incubation of vehicle or S18886 (Fig. 2E; P < 0.001) are shown in Figure 2. Changes in EC50 of Control + vehicle 24 ± 4 nM vs. Control + S18886 174 ± 3 nM (P < 0.01) and postpartum + vehicle 112 ± 4 nM vs. postpartum + S18886 22 ± 3 μM (P < 0.01) were calculated from data shown in Fig 2 D and E.

Figure 2.

Figure 2.

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A) Dose-response contraction to Thromboxane A2 receptor agonist U46619 in control (n = 6) and postpartum coronary arteries (n = 5). B) LogEC50 of U46610 concentration response. C) Diltiazem relaxations on U46619 and K+ contractions of control coronary arteries (n = 8). Inhibition of U46619-mediated contraction with TP receptor antagonist S18886 in control (D; n = 5) and postpartum (E; n = 5) coronary arteries. A) Two-way ANOVA with Student-Newman-Keul post-hoc test. B) Student t-test. *P < 0.05 vs. Control.

Additional preliminary studies were also performed to assess coronary responses to thromboxane A2 in vivo in control (n = 3) and postpartum (n = 2) swine. As previously reported [7], initial baseline coronary blood flow was lower in postpartum (~0.23 mL/min/g) compared to control (~0.55 mL/min/g) swine (Fig. 3A). Intracoronary administration of U46619 produced concentration-dependent reductions in coronary blood flow up to an ~45 ± 3% decrease at 1 μM U46619 in control swine. In contrast, coronary blood flow was unaffected by U46619 in postpartum swine (Fig. 3B).

Figure 3.

Figure 3.

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A) Individual coronary flow responses to intracoronary bolus injections of U46619 in control (n = 3) and postpartum (35–45 days post-delivery; n = 2) swine. B) Maximum change in coronary flow at maximum (1 μM) U46619 bolus intracoronary injection.

Response to coronary vascular smooth muscle depolarization

Receptor-independent coronary contraction was evaluated in isolated coronary arteries from control (n = 5) and postpartum (n = 5) swine by constructing concentration-response curves to KCl (5 – 90 mM). Vascular smooth muscle depolarization to KCl produced concentration-dependent contractions in both groups (Fig. 4A). While maximal contractions to 90 mM KCl were similar between control (125 ± 14 mN) and postpartum (134 ± 16 mN) arteries (P = 0.68), sensitivity to K+ induced depolarization was reduced in arteries from postpartum swine as the EC50 increased from 16 ± 1 mM in control to 22 ± 2 mM in postpartum swine (Fig. 4B, P < 0.05).

Figure 4.

Figure 4.

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A) Dose-response contractions to KCl in control (n = 5) and postpartum (n =5) coronary arteries. B) EC50 of KCl concentration response curves. A) Two-way ANOVA with Student-Newman-Keul post-hoc test. B) Student t-test. *P < 0.05 vs. Control.

DISCUSSION

Major findings of the study

Understanding the mechanisms that contribute to maternal vulnerability to cardiovascular complications in the postpartum period remains quite limited. Reductions in coronary flow reserve (reactivity) are recognized to be a powerful predictor of major adverse cardiovascular events [14] and thus a potential contributing factor to increased cardiovascular morbidity and mortality in postpartum period [15]. Based on recent studies supporting impaired control of coronary blood flow during this period [6, 7], we performed a series of experiments to test the hypothesis that coronary artery adaptations during the postpartum period after a healthy pregnancy are related to reductions in endothelium-dependent relaxation and/or augmented smooth muscle vasoconstrictor responsiveness. Our findings indicate that the postpartum period after a healthy pregnancy and delivery is associated with 1) normal load-dependent increases in coronary artery contraction; 2) reductions in endothelium-dependent coronary artery relaxation; 3) attenuated coronary artery contraction to thromboxane A2 receptor activation; 4) diminished sensitivity to smooth muscle depolarization-induced contractions. Together, these data demonstrate that the postpartum period is associated with reduced endothelium-dependent relaxation and coronary artery smooth muscle responsiveness to receptor-dependent and -independent vasoconstrictor pathways

Coronary artery reactivity in postpartum period

Pregnancy and the postpartum period are accompanied by significant temporal changes in systemic hemodynamics and circulating vasoactive factors [16, 17, 9]. How these alterations impact cardiac and coronary vascular function remains poorly defined. Recent reports of impaired coronary vasodilator responsiveness in humans [6] and diminished myocardial oxygen delivery in swine [7] in the postpartum period suggest these challenges lead to reductions in the ability of specific pathways to promote relaxation or increases in the capacity of alternative pathways to promote vasoconstriction. To begin to address this question we performed a series of studies in isolated coronary artery rings from control and postpartum swine (35–45 days post-delivery).

We first examined effects of changes in active tension development by incrementally increasing passive stretch (tension) followed by stimulation with KCl. Vessels were set to a passive tension for optimal active force development, as this is critical for comparing contractile responses from different animals. [18–20]. We observed similar contractions to KCl-induced depolarization relative to passive loading conditions in control and postpartum coronary arteries (Fig 1A). Although we were unable to provide actual measures of vessel diameter, these data demonstrate that the postpartum condition does not influence preload-dependent contraction of coronary smooth muscle.

Clinical studies indicate that adverse pregnancy outcomes are associated with endothelial dysfunction [21, 22] and attenuated vasodilator capacity of the coronary circulation [15]. However, the extent to which coronary endothelial dysfunction contributes to postpartum complications remains unclear. Studies in pregnant dogs show increased endothelium-dependent dilation compared to a nonpregnant group [23]. In contrast, studies of aortas from postpartum rats show decreased contraction to phenylephrine but no difference in methacholine-induced relaxation [24]. Our findings demonstrate marked reductions in maximal relaxation (Fig 1B) and sensitivity (Fig 1C) to bradykinin in coronary arteries from postpartum vs. control swine. We postulate this response is due to a reduction in the production of nitric oxide as prior evidence supports that the postpartum period is associated with increases in asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthesis inhibitor [25]. However, alterations in other vasoactive substances (prostaglandins, hyperpolarizing factors) and/or smooth muscle sensitivity to any of these factors could contribute. While such mechanisms have been investigated in other vascular beds (carotid and mesenteric) during pregnancy and postpartum, little is known regarding the coronary vasculature [11, 26]. Accordingly, additional studies to assess the effects of postpartum on coronary responses to a nitric oxide donor (sodium nitroprusside) along with interrogation of downstream signaling pathways and end-effector ions channels are warranted. Regardless, endothelium-dependent control predominately occurs in larger upstream arteries, thereby acting to preserve vasodilator reserve in downstream coronary resistance vessels [27]. Thus, the extent to which endothelial dysfunction functionally contributes to impaired control of coronary blood flow in postpartum hearts remains to be determined.

Effects of postpartum condition on coronary responses to thromboxane A2

Thromboxane A2 is an unstable arachidonic acid metabolite that promotes platelet aggregation and smooth muscle contraction [28]. Specifically, thromboxane A2 has been shown to produce variable degrees of coronary vascular contraction depending on underlying endothelial integrity and/or the presence of myocardial ischemia [29–33]. Prior studies in humans suggest that circulating concentrations of thromboxane A2 are elevated during healthy pregnancy and the early postpartum period (5–365 days post-delivery) [34, 35]. This elevation is exacerbated in pregnancies complicated by preeclampsia [17]. Elevated thromboxane A2 biosynthesis is observed at the end of pregnancy and throughout the postpartum period to support the hypercoagulable state of delivery and beyond [36, 37]. Accordingly, we postulated that coronary artery adaptations in postpartum hearts are related, at least in part, to increases in thromboxane A2 receptor signaling.

Our findings do not support this hypothesis as the sensitivity of the coronary circulation to the thromboxane A2 mimetic U46619 was attenuated both in vitro (Fig 2A) and in vivo (Fig 3) in postpartum vs. control swine. These data corroborate consistency between isometric tension studies of isolated arteries in vitro relative to microvascular responsiveness in vivo. Furthermore, our results are consistent with previous reports of diminished thromboxane A2-induced contraction in uterine, pulmonary, and skeletal muscle arteries in a variety of species during pregnancy [38, 37, 33, 39]. Similar maximal U46619-induced contractions with a rightward shift in EC50 (Fig 2B) indicates that alterations in the postpartum coronary circulation occur downstream of the thromboxane receptor (TP). Impairment of downstream TP signaling is supported by similar reductions in U46619-induced contractions to the TP receptor antagonist S18886 in control (Fig 2C) and postpartum (Fig 2D) arteries. These findings, along with results demonstrating U46619-mediated contractions are inhibited by the L-type Ca2+ channel inhibitor diltiazem suggest that pregnancy/postpartum period diminish Ca2+ sensitivity of coronary vascular smooth muscle [40].

Coronary Ca2+ sensitivity in postpartum period

TP receptor signaling occurs via inositol triphosphate-mediated increases intracellular [Ca2+] [28]. To assess the effects of the postpartum condition on the sensitivity of vascular smooth muscle to increases in intracellular [Ca2+] we examined concentration-dependent coronary responses to KCl. Essentially identical maximal coronary contractions to smooth muscle depolarization at 90 mM KCl (Fig 4A) indicates similar voltage-gated (L-type) Ca2+ channel abundance and activity in control and postpartum arteries. However, the increase in the EC50 of the KCl response (Fig 4B) implicates reductions in Ca2+ sensitivity in the postpartum coronary circulation. Our group has previously documented a role for voltage-gated K+ (KV) channels and electromechanical coupling with L-type Ca2+ channels in the control of coronary blood flow [41] and as pathway for coronary dysfunction in the setting of obesity [13]. To this end, augmented abundance or activity of smooth muscle KV channels in postpartum arteries could also contribute to the rightward shift of U46619 and KCl-induced coronary contractions. However, a prior study of uterine arteries found augmented myogenic tone was related to diminished, not augmented KV channel activity [42]. Further, studies in pregnant rat uterine arteries showed sensitivity to U46619-induced contraction was not different compared to nonpregnant controls, but the contribution of protein kinase C (PKC) and Rho kinase downstream signaling to these contractions were reduced in arteries from pregnant rats compared to nonpregnant controls [39]. Studies in smooth muscle cells suggest that TP receptor isoforms lead to different downstream functions in the contractile signaling pathway [43]. Swine have one identified TP receptor isoform that is most like the human TPα which is known for contributing to vascular tone through Rho signaling [44]. Taken together, the extent to which Ca2+ sensitivity, K+ channels and/or alterations in other potential signaling mechanisms (i.e., PKC, Rho/ROCK, MLCK) contribute to the postpartum coronary phenotype merits further investigation.

Limitations of the study

The disparity in weight between the control (50–60 kg) and postpartum (200–215 kg) swine is acknowledged and related to differences in age between the non-pregnant control group (~5 months) vs. the postpartum group (~18 months) as well as the weight gain associated with gestation (average litter size 14 piglets). This issue was extensively addressed in our recent in vivo study [7] wherein diminished coronary flow responses in postpartum swine were highly consistent with a study from the Di Carli’s laboratory in postpartum women [6]. This finding along with similarities in active-passive tension relationship (Fig 1A) and maximal coronary contractions to U46619 (Fig 2A) and K+ (Fig 4A) in control and postpartum coronary arteries support that differences in age and size of swine did not result in wholesale changes in coronary reactivity. We also acknowledge that the small sample size of the in vivo study (n = 2) as a limitation and for this reason did not perform/report any statistical analyses of these data. The intent of these initial studies was to provide preliminary evidence of the directional consistency between ex vivo isometric tension responses to U46619 in isolated coronary arteries and in vivo coronary flow responses to the same thromboxane A2 mimetic.

Implications and conclusions

In conclusion, our findings support that the postpartum period is associated with functional adaptations in the coronary circulation that attenuate endothelium-dependent relaxation as well as smooth muscle contraction. We speculate that these alterations are related to progressive changes in the postpartum vasoactive milieu that favor vasoconstriction. This reduced responsiveness could mitigate the possibility of an overcorrection in the increase in vascular resistance following delivery [35]. While literature detailing coronary reactivity during pregnancy and following delivery is sparse, recent data from our laboratory indicate that coronary blood flow and myocardial oxygen delivery are reduced in swine during the postpartum period [7]. Accordingly, decreases in sensitivity of coronary smooth muscle contraction could represent a protective adaptation, without which the risk of myocardial ischemia and adverse coronary events would be further increased. If this adaptation extends to the systemic circulation, it could mitigate a hypertensive response and adverse responses to circulating clotting factors known to be increased during pregnancy and the early postpartum period [36, 45]. Alternatively, it is important to recognize that reductions in sensitivity of smooth muscle contraction are not consistent with diminished myocardial perfusion [6, 7] and/or increases in postpartum mortality [46]. These findings suggest that chronic exposure of the coronary circulation to the pregnancy/postpartum milieu results in functional adaptations in sensitivity to paracrine/hormonal compounds that should be further explored.

Sources of Funding

This work was funded by the National Institutes of Health Grant R01 HL158723 and the American Heart Association Pre-Doctoral Fellowship Grant to SMT 23PRE1012811.

Footnotes

Disclosures

The authors have no conflicts of interest to disclose.

Statement of Ethics

The protocol for this investigation was approved by the University of North Texas Health Science Center Institutional Animal Care and Use Committee (IACUC 2023-0025, March 9, 2023) and performed in accordance with the Guide for the Care and Use of Laboratory Animals. No human participants were involved in this study.

Data Availability

The data that support the findings of this study are openly available via figshare at: https://doi.org/10.6084/m9.figshare.27941364.v1 Further enquiries can be directed to the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are openly available via figshare at: https://doi.org/10.6084/m9.figshare.27941364.v1 Further enquiries can be directed to the corresponding author.

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