Differential effects of cyclo-oxygenase 1 and 2 inhibition on angiogenesis inhibitor-induced hypertension and kidney damage. Issue 9 (13th May 2022)

• Record Type: Journal Article
• Authors: Mirabito Colafella, Katrina M.; van Dorst, Daan C.H.; Neuman, Rugina I.; Doorn, Leni van; Neves, Karla Bianca; Montezano, Augusto C.; Garrelds, Ingrid M.; van Veghel, Richard; de Vries, René; Uijl, Estrellita; Clahsen-van Groningen, Marian C.; Baelde, Hans J.; van den Meiracker, Anton H.; Touyz, Rhian M.; Visser, Willy; Danser, A.H. Jan; Versmissen, Jorie
• Is Part Of: Clinical science. Volume 136:Issue 9(2022)
• Page Start: 675
• Page End: 694
• Publication Date: 2022-05-13
• Subjects: cyclooxygenase -- endothelins -- hypertension -- NADPH oxidase -- vascular endothelial growth factor; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20220182
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days ( n =5–7/group). Our results demonstrated that prostacyclin (PGI2 ) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2 ) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.