BACKGROUND Cardiotoxicity is a major complication of anticancer therapy (CTx); however, the effect of CTx on the microcirculation is not well defined. This study evaluated the effect of CTx on microvascular function in patients with breast cancer (PwBC).METHODS Endothelial function and angiogenic potential were assessed in arterioles and adipose biopsies obtained from PwBC undergoing CTx (longitudinal and cross-sectional) and in healthy arterioles exposed to doxorubicin (Dox), trastuzumab (TZM), or paclitaxel (PTX) ex vivo. VEGF-B protein was used to test feasibility of targeted intervention.RESULTS PwBC treated with Dox and/or TZM developed profound microvascular endothelial dysfunction that persisted for ≥ 9 months after treatment cessation. Angiogenic potential was reduced during CTx and recovered within 1 month. Gene expression related to angiogenesis and inflammation changed over the course of clinical treatment. Adipose arterioles from healthy donors developed endothelial dysfunction when exposed to Dox or TZM ex vivo. PTX, which poses minimal cardiovascular risk, had no effect on vasomotor function. Ex vivo exposure to Dox or PTX suppressed angiogenic potential, whereas TZM had no effect. VEGF-B protein preserved endothelial function in arterioles exposed to Dox or TZM ex vivo.CONCLUSION PwBC undergoing treatment with Dox and/or TZM develop prolonged microvascular endothelial dysfunction that is recapitulated in healthy arterioles exposed to Dox or TZM ex vivo. Targeted intervention with VEGF-B protects against direct Dox- or TZM-induced vascular toxicity in human arterioles ex vivo.FUNDING NIH, American Heart Association, WeCare Foundation, Medical College of Wisconsin, Advancing a Healthier Wisconsin, Jenny and Antti Wihuri Foundation.

The non-canonical functions of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase play a critical role in maintaining microvascular homeostasis utilizing both human and rodent models. Previously, we have demonstrated that intact autophagic flux is necessary for the beneficial effects of TERT to maintain microvascular function and redox status in human resistance arterioles. The purpose of this investigation was to examine (1) whether loss of TERT function in vivo resulted in reductions in autophagy/mitophagy and concomitant changes in the mediator of microvascular FMD; (2) whether restoration of autophagy can reverse this pathological switch in dilator mechanism, reduce shear-induced mitochondrial H2O2 production while enhancing NO production. TERT mutant rats were generated and compared to their WT counterparts. Rats were given an autophagy activator (2% trehalose) for 28-days. Isolated mesenteric arteries were used for videomicroscopy, and aortic tissue was collected for immunoblotting. FMD and autophagic flux were measured in arteries in all groups. Loss of TERT function resulted in a switch from NOS-dependent to H2O2-dependent FMD, repressed microvascular shear-induced autophagic flux and NO production, and increased mitochondrial H2O2 production. Activation of autophagy restored NO-mediated dilation in TERT mutant rats, and enhanced shear-induced autophagic flux. We provide evidence that autophagy is necessary for the beneficial role of TERT within maintaining microvascular function, positioning this pathway as a modifiable target to maintain microvascular health by rescuing the endothelial dysfunction caused by loss of TERT signaling.

INTRODUCTION:A previous study found that following out-of-hospital cardiac arrest (OHCA), 67% of out-of-hospital 12-lead electrocardiograms (ECGs) diagnostic for ST-segment elevation myocardial infarction (STEMI) changed to non-STEMI on repeat emergency department (ED) ECG. Here we evaluated associations with resolution of STEMI on ED ECG. METHODS:In this secondary analysis of a previous retrospective study, adults (≥18 years) with return of spontaneous circulation (ROSC) following OHCA, at least 1 out-of-hospital and ED ECG and transport to the study hospital were entered. We analyzed variables suspected of influencing ischemic changes on ECG including arrest characteristics, treatment interventions, resuscitation duration, and out-of-hospital and ED ECG acquisition times. RESULTS:Forty-nine of 176 patients entered had out-of-hospital ECGs diagnostic for STEMI, and 33/49 (67%) had resolved STEMI upon ED evaluation. Shorter resuscitation time (13 [interquartile range 5-18] vs 21 [14-28] minutes), p = 0.007), less epinephrine (3 [1-4] vs 5 [2-10] milligrams, p = 0.018), lower incidence of norepinephrine (5/33 (15%) vs 11/16 (69%), p ≤ 0.001), less time from ROSC to out-of-hospital ECG acquisition (5.5 [1-8] vs 8.5 [7-14] minutes, p = 0.044), and more time between out-of-hospital and ED ECG acquisition (34 [25-52] vs 21 [14-27] minutes, p = 0.001) were associated with resolution of out-of-hospital STEMI on ED evaluation. More defibrillations were associated with increased ischemia on ED ECG for patients with non-STEMI out-of-hospital ECGs. CONCLUSION:ROSC patients with STEMI on out-of-hospital ECG commonly resolve in the ED (67%). These identified associations may better inform clinical decision making. Post-ROSC out-of-hospital 12-lead ECGs should be repeated on arrival in the ED.

Introduction: Endothelial dysfunction drives cardiovascular disease, with acute stressors like high glucose (HG) or intraluminal pressure (IILP) by reducing nitric oxide (NO) and increasing hydrogen peroxide (H 2 O 2 ). Mitochondrial fission amplifies ROS, while fusion mitigates it. Hypoxic preconditioning (HPC) may shift mitochondrial dynamics from fission to fusion under stress, potentially restoring endothelial function and reducing damage. METHOD: Endothelial cells (HUVECs) were exposed to HG (22 mM) or normal glucose (NG; 5.5 mM) for 15–20 hours. Human arterioles from healthy adipose tissue were isolated for video microscopy. Internal diameters were measured after increases in intraluminal pressure gradients (flow), with/without NOS inhibitor (L-NAME, 100 μM) or H 2 O 2 scavenger (Peg-Catalase, 500 U/mL). HPC was performed on separate groups of cells (prior to HG;2-hour hypoxia/normoxia cycles) and arterioles, (Prior to IILP three 30-minute cycles of hypoxia -5% O 2 and normoxia -21% O 2 ). Controls underwent no gas changes. Mitochondrial networks were imaged via confocal microscopy, fragmentation quantified (MFC; particles/pixel x 1000). Drp-1 (S616) and MFN-2 were analyzed by western blot. Molecular data are mean ± SEM; vascular data as % dilation; significance set at P < 0.05. Result: Exposure to HG significantly increases the MFC (n=2, p<0.05) compared to NG. HPC effectively preserve the mitochondrial phenotype. Western blot analysis revealed a significant reduction in Drp-1 pS616 levels, while MFN-2 levels were significantly increased (p<0.05) in cells subjected to HPC prior to high glucose treatment, compared to NG-treated cells. HG exposure elevated Drp-1 pS616, and reduced MFN-2 protein expression, while exposure to HPC reversed these effects ( insert values and or p-values ). Exposure to IILP was associated with a switch in FMD from NO to H2O2, while HPC prevented this switch (p<0.05)). Inhibition of MFN-2 via siRNA (50 nM) prevented the restorative effects of HPC, maintaining H2O2-mediated dilation following IILP ((p<0.05)). Conclusion: This study shows that acute stressors induce mitochondrial fission and microvascular dysfunction, while HPC preserves mitochondrial fusion and endothelial function. Funded by R01-HL133029-05 (AMB), R01-HL157025-01 (DDG), and R01-HL135901-04 (DDG), K99-HL161491 (WEH) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

This study defines the mechanisms of vasodilation to acetylcholine (ACh) in arterioles from patients with and without coronary artery disease (CAD). Human adipose arterioles (HAA) dissected from discarded surgical samples were cannulated and pressurized at 60 mmHg for measurement of diameter changes by videomicroscopy. No difference in baseline dose response to ACh was observed between non-CAD and CAD patients. L-NAME, NO synthase inhibitor, reduced dilation in both groups but to a greater extent in non-CAD. Peg-CAT, H2O2 scavenger, attenuated response to ACh in non-CAD but not in CAD. Inhibition of NOX4 reduced dilation in non-CAD, whereas NOX2 inhibition attenuated dilation in CAD. The SOD mimetic tempol partially normalized the NO- and H2O2-dependent dilation in CAD arterioles. EPR spin trapping indicated that absolute NO signal after ACh + A-23187 stimulation was higher in non-CAD than in CAD arteries. Western blot analysis revealed higher expression of monomeric eNOS but lower expression of dimeric eNOS and phosphorylated eNOS at Ser-1177 in CAD arteries. Finally, we found higher mRNA and protein expression of NOX2 in CAD arteries. These results provide new evidence that in normal human arterioles, both NO and H2O2 significantly contribute to ACh dilation, with substantial involvement of NOX4 in the H2O2-mediated response. In CAD, the contribution of both NO and H2O2 is diminished, while an NO/H2O2-independent hyperpolarizing pathway becomes predominant. Mechanistically, the NOX4-to-NOX2 switch may play a key role in mediating the change of vasodilator mechanisms in human arterioles during CAD.

Cardiotoxicity is a significant challenge associated with common first-line breast cancer (BC) anti-neoplastic (CTx) treatments including anthracyclines (AC) and targeted immunotherapies, such as anti-Her-2 therapy. Non-Hispanic black/African American (NHB) women are at higher risk for CTx induced cardiotoxicity compared to Non-Hispanic White (NHW) women. To date, most study efforts to mitigate cardiotoxicity target large vessels and cardiac damage. However, impaired microvascular function may also be implicated. Further, although exercise interventions reduce systemic inflammation and cardiovascular risk, few cardio-oncology studies examine the effect of exercise on CTx cardiotoxicity, and none have quantified microvascular endothelial function. An additional gap is the paucity of studies focused on racial disparities. The Discovery and Elimination of Cardio-Oncology Disparities for Equity in the Heartland (DECODE Heartland) Center addresses these gaps with three overarching goals to: (1) Test the feasibility and efficacy of the Take Charge during Treatment (TCT) exercise intervention designed to mitigate the adverse effects of CTx; (2) Quantify differences on exercise capacity and quality of life (QoL), endothelial function and molecular differences in inflammation in NHB versus NHW BC patients before and following CTx; and (3) Examine the influence of socio-ecological factors (individual, interpersonal, systemic, environmental) on inflammation, microvascular endothelial function, QoL in response to the exercise intervention. NHB and NHW women diagnosed with non-metastatic BC, scheduled to receive AC and/or anti-Her2 therapy, will be recruited and randomized to participate in the TCT intervention or usual care. TCT is a virtual exercise program with weekly coaching sessions, six of which include supervised exercise. Assessments include surveys, dual X-ray absorptiometry, flow-mediated dilation, pulse wave velocity and analysis, VO2 peak cycling test, fat biopsy, venous puncture blood draw, geocoding of patient addresses, and measurement of neighborhood characteristics. Assessments will be captured prior to treatment, post-intervention (16-20 weeks), and at follow-up/study completion (12-18 months post-diagnosis). This study reflects a first step in a research trajectory to identify upstream determinants of disparities and discern how behavioral strategies can assist diverse BC survivors to move through treatment toward better health, including reduced rates of cardiotoxicity following anti-cancer treatment.

Endothelial microvascular dysfunction affects multi-organ pathologic processes that contribute to increased vascular tone and is at the base of impaired metabolic and cardiovascular diseases. The vascular dilation impaired by nitric oxide (NO) deficiency in such dysfunctional endothelium is often balanced by endothelial-derived hyperpolarizing factors (EDHFs), which play a critical role in managing vascular tone. Our latest research has uncovered a new group of lactone oxylipins produced in the polyunsaturated fatty acids (PUFAs) CYP450 epoxygenase pathway, significantly affecting vascular dilation. The lactone oxylipin, derived from arachidonic acid (5,6-diHET lactone, AA-L), has been previously shown to facilitate vasodilation dependent on the endothelium in isolated human microvessels. The administration of the lactone oxylipin derived from eicosapentaenoic acid (5,6-diHETE lactone, EPA-L) to hypertensive rats demonstrated a significant decrease in blood pressure and improvement in the relaxation of microvessels. However, the molecular signaling processes that underlie these observations were not fully understood. The current study delineates the molecular pathways through which EPA-L promotes endothelium-dependent vascular dilation. In microvessels from hypertensive individuals, it was found that EPA-L mediates endothelium-dependent vasodilation while the signaling pathway was not dependent on NO. In vitro studies on human endothelial cells showed that the hyperpolarization mediated by EPA-L relies on G-protein-coupled receptor (GPR)-phospholipase C (PLC)-IP3 signaling that further activates calcium-dependent potassium flux. The pathway was confirmed using a range of inhibitors and cells overexpressing GPR40, where a specific antagonist reduced the calcium levels and outward currents induced by EPA-L. The downstream AKT and endothelial NO synthase (eNOS) phosphorylations were non-significant. These findings show that the GPR-PLC-IP3 pathway is a key mediator in the EPA-L-triggered vasodilation of arterioles. Therefore, EPA-L is identified as a significant lactone-based PUFA metabolite that contributes to endothelial and vascular health.

Understanding post-stroke changes in skeletal muscle oxidative metabolism and microvascular reactivity could help create therapeutic targets that optimize rehabilitative interventions. Due to disuse atrophy, we hypothesized that basal muscle oxygen consumption rate and microvascular endothelial function would be impaired in the tibialis anterior (TA) muscle of the affected leg of chronic stroke survivors compared with the nonaffected leg and versus matched controls. Fifteen chronic stroke survivors (10 females) and 15 matched controls (9 females) completed this study. A near-infrared spectroscopy oximeter measured tissue oxygen saturation (StO2) of the TA in both legs of stroke survivors and the dominant leg of controls. A cuff was placed around the thigh and inflated to 225 mmHg for 5 min while StO2 was continuously measured. The rate of change in StO2 was calculated during cuff occlusion and immediately post-cuff release. The rate of oxygen desaturation was similar between the legs of the stroke survivors (paretic -0.12 ± 0.04%·s-1 vs. nonparetic -0.16 ± 011%·s-1; P = 0.49), but the paretic leg had a reduced desaturation rate versus controls (-0.25 ± 0.18%·s-1; P = 0.007 vs. paretic leg). After cuff release, there was a greater oxygen resaturation rate in the nonparetic leg compared with the paretic leg (3.13 ± 2.08%·s-1 vs. 1.60 ± 1.11%·s-1, respectively; P = 0.01). The control leg had a similar resaturation rate versus the nonparetic leg (control = 3.41 ± 1.79%·s-1; P = 0.69) but was greater than the paretic leg (P = 0.003). The TA in the paretic leg had an impaired muscle oxygen consumption rate and reduced microvascular endothelial function compared with controls.NEW & NOTEWORTHY Secondary consequences of stroke are not well described. In this study, we show that basal muscle oxidative consumption and microvascular endothelial function are reduced in the paretic tibialis anterior muscle of chronic stroke survivors compared with matched controls using near-infrared spectroscopy and the vascular occlusion technique. There was a moderately strong correlation between microvascular endothelial function and paretic leg strength.

Background: Few studies have examined changes in skeletal muscle physiology post-stroke. This study examined changes in tissue oxygen saturation (StO(2)) of the vastus lateralis (VL) muscle of stroke survivors and age-matched control participants during maximal and submaximal isometric contractions of the knee extensor muscles. Objectives: We hypothesized that tissue oxygen desaturation (Delta StO(2)) during knee extensor muscle contractions would be less in the VL in the paretic vs. the non-paretic and control legs. Methods: Ten chronic stroke survivors (>6 months post-stroke) with lower extremity muscle weakness and 10 age-matched controls completed this prospective cohort study. Maximum voluntary contractions (MVCs) of the knee extensor muscles were assessed with a Biodex dynamometer and StO(2) of the VL was measured using near-infrared spectroscopy. Results: In the paretic leg of the stroke survivors little change in StO(2) of the VL was observed during an MVC (Delta StO(2) = -1.7 +/- 1.8%) compared to the non-paretic (Delta StO(2) = -5.1 +/- 6.1%; p < 0.05) and control legs (Delta StO(2) = -14.4 +/- 8.8%; p < 0.05 vs. paretic and non-paretic leg). These differences remained when normalizing for strength differences between the legs. Compared to controls, both the paretic and non-paretic VL showed pronounced reductions in Delta StO(2) during ramp and hold contractions equal to 20%, 40%, or 60% of the MVC (p < 0.05 vs. controls at all load levels). Conclusions: These results indicate that oxygen desaturation in response to isometric muscle contractions is impaired in both the paretic and non-paretic leg muscle of stroke survivors compared to age-matched controls, and these differences are independent of differences in muscle strength.

We have previously shown that endothelial function in the human placental microcirculation is impacted by excessive oxidative stress and TLR9 may be part of this mechanism. Therefore, to evaluate whether TLR9 knockdown restores vascular function in preeclamptic microvessels. Placental microvessels (< 150μM diameter) were dissected from the maternal side of control or preeclamptic placentas and then incubated with media and scrambled siRNA or TLR9-specific siRNA (50nM) for 12-16 hours. Vessels were cannulated on glass micropipettes, pressurized to 60mmHg, and then pre-constricted with 0.1-2.0 nM endothelin-1. A pressure gradient was applied to induce flow and vessel inner diameters were measured by videomicroscopy. Flow-mediated dilation (FMD) was calculated as a % of maximum diameter and expressed as mean ± SEM. Results were analyzed by two-way ANOVA with Dunnett’s multiple comparisons. The maximum dilation values were evaluated by a Kruskal-Wallis test with Dunn’s multiple comparative test or t-test as appropriate. Preeclamptic microvessels demonstrated impaired endothelium-dependent vasodilation compared to healthy controls (Fig. A, p=0.0018). Vasodilator capacity in healthy controls was not significantly impacted by siRNA treatment (Fig. B, p=0.4429). TLR9 siRNA restored impaired endothelium-dependent vasodilation to flow compared to both untreated and scrambled siRNA-transfected vessels from patients with preeclampsia (Fig. C, p=0.0082). Suppression of TLR9 expression restores endothelium-dependent vasodilation to flow in preeclamptic vessels and merits further evaluation.

Abstract Nearly 4 million breast cancer survivors live in the United States (U.S.). Continued improvements of cancer therapies (CTx), including targeted treatment options such as anti-HER2 therapy combined with traditional systemic CTx like anthracyclines (ANTs) have made adverse cardiovascular events the leading cause of non-cancer related mortality among BC survivors. Toxicities can be acute and/or reversible (e.g., anti-her2) or may persist for years (ANTs)). Most efforts focus on managing and defining the mechanism of cardiac damage in response to CTx. Yet, systemic vascular function, including microvascular endothelial function, is not only a predictor but also a contributor to a significant number of cardiovascular complications that is mostly overlooked in response to CTx. Little to no mechanistic evidence exists how CTx impacts the human circulation and endothelial function. Systemic inflammation (e.g., Interleukin levels or TLR signaling) is elevated in cancer and CV disease alike, yet the connection of CTx induced endothelial dysfunction has not been explored in breast cancer patients. Black/African American women are at higher risk for cardio-toxicity. Existing literature suggest significant racial differences in immune signaling and microvascular function perhaps explaining varying risk for CV toxicity post-CTx. However, contributing biological, social and environmental factors remain ill defined. The Discovery and Elimination of Cardio-Oncology Disparities for Equity (DECODE) in the Heartland center addresses critical gaps in the literature by testing if an exercise intervention can lower systemic inflammatory load to improve endothelial function and CV risk itself. We propose to: 1) quantify physiological and molecular differences in inflammation and endothelial function before and following CTx among 120 Black/African American and non-Hispanic White women with invasive, non-metastatic BC; 2) test the feasibility and efficacy of an exercise intervention during CTx designed to mitigate the adverse effects of treatment on exercise capacity and QoL; and 3) examine the influence of multi-level socio-ecological factors (individual, interpersonal, institutional, environmental) on inflammation, microvascular endothelial function, QoL and response to the exercise intervention among participants. This presentation presents DECODE’s novel translational study design and methodologies. Citation Format: Melinda Stolley, Andreas Beyer, Kirsten Beyer, Alison Kriegel, David Gutterman, Shane Phillips, Sherry Ann Brown, Kent Hoskins, Rodney Sparapani, Michael Widlansky, Amanda Kong. Understanding and addressing disparities in cancer therapy induced inflammation and associated endothelial dysfunction [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B022.

Microvascular dysfunction predicts adverse cardiovascular events despite absence of large vessel disease. A shift in the mediator of flow-mediated dilatation (FMD) from nitric oxide (NO) to mitochondrial-derived hydrogen peroxide (H2O2) occurs in arterioles from patients with coronary artery disease (CAD). The underlying mechanisms governing this shift are not completely defined. Lipid phosphate phosphatase 3 (LPP3) is a transmembrane protein that dephosphorylates lysophosphatidic acid, a bioactive lipid, causing a receptor-mediated increase in reactive oxygen species. A single nucleotide loss-of-function polymorphism in the gene coding for LPP3 (rs17114036) is associated with elevated risk for CAD, independent of traditional risk factors. LPP3 is suppressed by miR-92a, which is elevated in the circulation of patients with CAD. Repression of LPP3 increases vascular inflammation and atherosclerosis in animal models. We investigated the role of LPP3 and miR-92a as a mechanism for microvascular dysfunction in CAD. We hypothesized that modulation of LPP3 is critically involved in the disease-associated shift in mediator of FMD. LPP3 protein expression was reduced in left ventricle tissue from CAD relative to non-CAD patients (P = 0.004), with mRNA expression unchanged (P = 0.96). Reducing LPP3 expression (non-CAD) caused a shift from NO to H2O2 (% maximal dilatation: Control 78.1 & PLUSMN; 11.4% vs. Peg-Cat 30.0 & PLUSMN; 11.2%; P < 0.0001). miR-92a is elevated in CAD arterioles (fold change: 1.9 & PLUSMN; 0.01 P = 0.04), while inhibition of miR-92a restored NO-mediated FMD (CAD), and enhancing miR-92a expression (non-CAD) elicited H2O2-mediated dilatation (P < 0.0001). Our data suggests LPP3 is crucial in the disease-associated switch in the mediator of FMD.

Objective: To determine if placental vessel endothelial dysfunction can be produced in control vessels by exposure to preeclamptic plasma, establishing a model to further explore the mechanisms of dysfunction and therapeutics to restore function in preeclampsia. Hypothesis: Preeclamptic plasma administered to unaffected vessels induces endothelial dysfunction. Methods: Placental microvessels were dissected from the maternal side of placentas from patients consented to the Medical College of Wisconsin Maternal Research Placenta and Cord Blood Bank. Control vessels were treated with 10% healthy maternal plasma or 10% preeclamptic (PreE) maternal plasma within the vessel lumen for 12-16 hours[MJ1]. PreE vessels were not treated with plasma. Microvessels were then cannulated on glass micropipettes, pressurized to 60mmHg and constricted with 0.1-1.0 nM Endothelin-1 (ET-1). A 1-100cm H2O pressure gradient was applied and the inner diameter of the vessel was measured by video microscopy. The change in diameter was calculated as a % of maximum diameter as assessed by exposure to 100μM papaverine. Flow mediated dilation (FMD) was evaluated by a two-way ANOVA test with Dunnett’s multiple comparisons. The maximum dilation values were evaluated by a Kruskal-Wallis test with Dunn’s multiple comparative test or t-test as appropriate. FMD is evaluated as mean +/- SEM. Data: Control vessels at maximum flow dilated to 81.1 % ± 7.1 % (n=5), whereas vessel from PreE placentas dilated to 36.9 % ± 8.6% (n=3,). Incubation of control vessels with normal plasma resulted in maximal dilation of 80.6% ± 3.3%, n=3. Control vessels incubated with plasma from PreE patients dilated to 44.7% ± 4.7%. n=3). Summary of Results: Control vessels dilated significantly more than PreE vessels when evaluated by t-test (p=0.05). Incubation of control vessels with normal plasma did not change maximal dilation (p>0.99). Control vessels incubated with PreE plasma demonstrated a near significant drop in dilatory capacity (p=0.05). PreE plasma exposed vessels compared to untreated PreE vessels showed no significant difference (p=0.46[DDG2] ).When comparing overall flow mediated dilatory responses in these vessels there is a significant difference observed between control vessels, control vessels treated with PreE plasma, and PreE vessels at 50cm H2O (p<0.05). This difference is even more significant (p<0.01) at the maximum pressure gradient when analyzed by two-way ANOVA. There is no significant difference at any point between control vessels and control vessels treated with normal plasma as evaluated by two-way ANOVA (p>0.99). Conclusions: The addition of PreE plasma to control vessels demonstrates similar impairment in endothelium-dependent vasodilation as seen in untreated PreE vessels. Future directions will include evaluation of the mechanisms of vasodilation and therapeutic options that could restore endothelial function in PreE vessels. NHLBI 1K08HL150340-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Recent strides in anti-cancer therapeutics have improved longevity and led to a growing population of cancer survivors, who are increasingly likely to die of other causes. Treatment-induced cardiotoxicity is a complication of several therapeutic agents with acute and long-term consequences for cancer patients. Vascular endothelial dysfunction is a precursor and hallmark of ischemic coronary disease and may play a role in anti-cancer therapy-induced cardiotoxicity. This review summarizes clinical evidence for endothelial dysfunction following anti-cancer therapy and extends the discussion to include the impact of therapeutic agents on conduit arteries and the microcirculation. We highlight the role of innate immune system activation and cross-talk between inflammation and oxidative stress as pathogenic mechanisms underlying anti-cancer therapy-induced vascular toxicity. Understanding the impact of anti-cancer agents on the vascular endothelium will inform therapeutic approaches to prevent or reverse treatment-induced cardiotoxicity and may serve as an important tool to predict, monitor, and prevent adverse cardiovascular outcomes in patients undergoing treatment.

Purpose: This study examined tissue oxygen saturation (StO2) of the vastus lateralis (VL) muscles of chronic stroke survivors during a graded exercise test (GXT). We hypothesized that the reduction in StO2 will be blunted in the paretic versus nonparetic VL during a maximum effort GXT. Methods: Chronic stroke survivors performed a GXT, and StO2 of the VL in each leg was measured using near-infrared spectroscopy. Twenty-six stroke survivors performed a GXT. Results: At rest, there was no difference in StO2 between the paretic and nonparetic VL (65 ± 9% vs 68 ± 7%, respectively, P = .32). The maximum change in StO2 from rest during the GXT was greater in the nonparetic versus the paretic VL (−16 ± 14% vs −9 ± 10%, respectively, P < .001). The magnitude of the oxygen resaturation response was also greater in the nonparetic versus the paretic VL (29 ± 23% vs 18 ± 15%, respectively, P < .001). VO2 peak was associated with the magnitude of the VL StO2 change during (r2 = 0.54, P < .0001) and after (r2 = 0.56, P < .001) the GXT. Conclusion: During a GXT, there is a blunted oxygen desaturation response in the paretic versus the nonparetic VL of chronic stroke survivors. In the paretic VL, there was a positive correlation between the oxygen desaturation response during the GXT and VO2 peak.

Advanced age is a well‐documented risk factor for coronary microvascular dysfunction. Recent evidence has underscored that advanced age is associated with a shift toward greater mitochondrial fission rather than mitochondrial fusion. Therefore, understanding key regulators of the balance of mitochondrial fission/fusion may help to identify the contribution of mitochondrial dynamics on microvascular endothelial function. DRP1 is a pro‐fission factor that has been linked to several disease manifestations including advanced age and cardiovascular disease (CVD).