Selected Grantee Publications
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- 2 results found
- nhgri
- nibib
- Cardiovascular
Identifying Mitigating Strategies for Endothelial Cell Dysfunction and Hypertension in Response to VEGF Receptor Inhibitors
Camarda et al., Clinical Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39282930/
Vascular endothelial growth factor receptor inhibitor (VEGFRi) use can improve survival in patients with advanced solid tumors, but outcomes can worsen because of VEGFRi-induced hypertension, which can increase the risk of cardiovascular mortality. The underlying pathological mechanism is attributed to endothelial cell (EC) dysfunction. The researchers performed phosphoproteomic profiling on human ECs and identified α-adrenergic blockers, specifically doxazosin, as candidates to oppose the VEGFRi proteomic signature and inhibit EC dysfunction. In vitro testing of doxazosin with mouse, canine, and human aortic ECs demonstrated EC-protective effects. In a male C57BL/6J mouse model with VEGFRi-induced hypertension, it was demonstrated that doxazosin prevents EC dysfunction without decreasing blood pressure. In canine cancer patients, both doxazosin and lisinopril improve VEGFRi-induced hypertension. This study demonstrates the use of phosphoproteomic screening to identify EC-protective agents to mitigate cardio-oncology side effects. Supported by ORIP (K01OD028205), NCI, NHGRI, and NIGMS.
Mineralocorticoid Receptor Blockade Normalizes Coronary Resistance in Obese Swine Independent of Functional Alterations in Kv Channels
Goodwill et al., Basic Research in Cardiology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34018061/
Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening. Supported by ORIP (U42OD011140, S10OD023438), NHLBI, and NIBIB.