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The vascular endothelium plays a crucial role to regulate vascular tone. Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is known to cause vascular endothelial dysfunction. However, the long‐term effects of SARS‐CoV‐2 in resistance vessels remains unknown. This study is designed to test whether endothelium‐dependent vasodilation in human arterioles remains impaired after clearance of SARS‐CoV‐2 virus. Fresh human adipose tissues were obtained as discarded surgical specimens from control subjects (n=15, no SARS‐CoV‐2 exposure, 46.7±4 years) and previously SARS‐CoV‐2 positive subjects (PSPSs: n=8, 35.8±3.8 years). Among PSPSs, the time between positive and negative SARS‐CoV‐2 test results was ≤3 months (n=6) or 8 months (n=2). Isolated arterioles (100‐200 µm) were cannulated under 60 mmHg and examined for diameter changes to acetylcholine (ACh; 10−9 to 10−5 M) and sodium nitroprusside (SNP: 10−9 to 10−4 M) using videomicroscopy. Flow‐mediated dilation (FMD) was recorded at steady‐state during graded increases in intraluminal pressure gradients (5‐100 cm H2O). Dilation to ACh and FMD in arterioles from PSPSs was significantly reduced (ACh max. dilation at 10−5 M: 60±6% vs. 92.8±3.9% in control, n=7‐8, P

OBJECTIVE: Treatment with BCR-ABL tyrosine kinase inhibitors (TKIs) is the standard of care for patients with chronic myeloid leukemia, however evidence indicates these compounds may have cardiovascular side-effects. This study sought to determine if ex vivo exposure of human adipose arterioles to the BCR-ABL TKIs imatinib and nilotinib causes endothelial dysfunction. METHODS: Human adipose arterioles were incubated overnight in cell culture media containing vehicle (PBS), imatinib (10 μmol/L) or nilotinib (100 μmol/L). Arterioles were cannulated onto glass pipettes and flow mediated dilation (FMD) was assessed via video microscopy. To determine the mechanism of vasodilation, FMD was re-assessed in the presence of either the nitric oxide synthase inhibitor L-NAME (100 μmol/L) or the H(2)O(2) scavenger PEG-Catalase (500 U/mL). RESULTS: Neither imatinib nor nilotinib affected the magnitude of FMD (max dilation = 78±17% vehicle, 80 ± 24% nilotinib, 73 ± 13% imatinib). FMD was decreased by L-NAME in vehicle-treated arterioles (max dilation = 47±29%). Conversely, L-NAME had no effect on FMD in imatinib- or nilotinib-treated vessels (max dilation = 79±14% and 80 ± 24%, respectively), rather FMD was inhibited by PEG-Catalase (max dilation = 29±11% and 29 ± 14%, respectively). CONCLUSION: Incubating human arterioles with imatinib or nilotinib switches the mediator of FMD from vasoprotective nitric oxide to pro-inflammatory H(2)O(2).

Chemotherapy (CT) is a necessary treatment to prevent the growth and survival of cancer cells. However, CT has a well-established adverse impact on the cardiovascular (CV) system, even years after cessation of treatment. The effects of CT drugs on tumor vasculature have been the focus of much research, but little evidence exists showing the effects on the host microcirculation. Microvascular (MV) dysfunction is an early indicator of numerous CV disease phenotypes, including heart failure. The goal of this study was to evaluate the direct effect of doxorubicin (Dox) on human coronary MV function. To study the effect of CT on the cardiac MV function, flow-mediated dilation (FMD), pharmacologically-induced endothelial dependent dilation to acetylcholine (ACh), and smooth muscle-dependent dilation to papaverine were investigated. Vessels were freshly isolated from atrial appendages of adult patients undergoing cardiopulmonary bypass surgery or from cardiac tissue of pediatric patients, collected at the time of surgery to repair congenital heart defects. Isolated vessels were incubated in endothelial culture medium containing vehicle or Dox (100 nm, 15–20 h) and used to measure dilator function by video microscopy. Ex vivo treatment of adult human coronary microvessels with Dox significantly impaired flow-mediated dilation (FMD). Conversely, in pediatric coronary microvessels, Dox-induced impairment of FMD was significantly reduced in comparison with adult subjects. In both adult and pediatric coronary microvessels, ACh-induced constriction was reversed into dilation in the presence of Dox. Smooth muscle-dependent dilation remained unchanged in all groups tested. In vessels from adult subjects, acute treatment with Dox in clinically relevant doses caused significant impairment of coronary arteriolar function, whereas vessels from pediatric subjects showed only marginal impairment to the same stressor. This interesting finding might explain the delayed onset of future adverse CV events in children compared with adults after anthracycline therapy. NEW & NOTEWORTHY We have characterized, for the first time, human microvascular responses to acute ex vivo exposure to doxorubicin in coronary vessels from patients without cancer. Our data show an augmented impairment of endothelial function in vessels from adult subjects compared with pediatric samples.