Abstract 1078: A Cross-species Platform And Phosphoproteomics Analysis To Mitigate Vegfri-induced Hypertension And Endothelial Dysfunction

• DOI: 10.1161/atvb.44.suppl_1.1078
• Publication Date: 2024-07-24T13:03:55Z
• Authors: Nicholas D Camarda; Qing Lu; Joshua Man; Gregory Martin; Richard J Travers; Katherine E Lopez; Dawn M Meola; Sarah N Powers; Zeyuan Song; Malvina Papanasta...; Katherine DeRuff; James Mullahoo; Shawn Egri; Desiree Davison; Scott Eblen; Jacob Jaffe; Gordon Huggins; Cheryl London; Jenica Upshaw; Vicky Yang; Iris Z Jaffe
• Keywords: Endothelial Dysfunction; Phosphoproteomics

Introduction: Vascular endothelial growth factor receptor inhibitors (VEGFRis) are a class of tyrosine kinase (TKIs) used to treat human and canine cancers, but these drugs also cause hypertension (HTN) cell (EC) dysfunction. Purpose: We combined phosphoproteomic analysis in ECs with cross-species in-vitro in-vivo approach identify mitigating therapies for VEGFRi-induced EC dysfunction HTN. Methods Results: developed sorafenib-induced HTN mouse model showing increased blood pressure, mesenteric resistance vessel (decreased phosphorylation Ser1177 on nitric oxide synthase [p-eNOS], endothelin-1 [ET-1]), renal glomerular endotheliosis. Human umbilical vein were treated VEGFR TKIs, non-VEGFR cardiovascular drugs. Phosphoproteomic mass spectrometry marker selection algorithm identified 14-phosphopeptide signature differentiating TKIs from TKIs. The peptide RBM17 pS222 VEGFRi treatment human, canine, aortic ECs, correlating reduced p-eNOS. By screening that reverse the signature, we found alpha-adrenergic antagonists, particularly doxazosin, had most anti-correlated signatures. Doxazosin prevented primary across species. In mice, doxazosin reversed vessels without affecting pressure or Conversely, lisinopril endotheliosis not Preliminary results our clinical trial cancer patients confirmed toceranib induced showed both significantly lowered dogs Conclusion: Our study demonstrates utility phosphoproteomics identifying EC-protective effects data suggest distinct mechanisms HTN, potentially involving damage.