Differential effects of cyclo-oxygenase 1 and 2 inhibition on angiogenesis inhibitor-induced hypertension and kidney damage

Colafella, Katrina M.Mirabito and van Dorst, Daan C.H. and Neuman, Rugina I. and van Doorn, Leni and Neves, Karla Bianca and Montezano, Augusto C. and Garrelds, Ingrid M. and van Veghel, Richard and de Vries, René and Uijl, Estrellita and Clahsen-Van Groningen, Marian C. and Baelde, Hans J. and van den Meiracker, Anton H. and Touyz, Rhian M. and Visser, Willy and Jan Danser, A. H. and Versmissen, Jorie (2022) Differential effects of cyclo-oxygenase 1 and 2 inhibition on angiogenesis inhibitor-induced hypertension and kidney damage. Clinical Science, 136 (9). pp. 675-694. ISSN 0143-5221 (https://doi.org/10.1042/CS20220182)

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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.

ORCID iDs

Colafella, Katrina M.Mirabito, van Dorst, Daan C.H., Neuman, Rugina I., van Doorn, Leni, Neves, Karla Bianca ORCID logoORCID: https://orcid.org/0000-0001-5158-9263, 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, Jan Danser, A. H. and Versmissen, Jorie;
CORE (COnnecting REpositories)