The contribution of VEGF signalling to fostamatinib‐induced blood pressure elevation

Abstract

BACKGROUND AND PURPOSEFostamatinib is an inhibitor of spleen tyrosine kinase (TK). In patients, fostamatinib treatment was associated with increased BP. Some TK inhibitors cause BP elevation, by inhibiting the VEGF receptor 2 (VEGFR2). Here, we have assessed the mechanistic link between fostamatinib-induced BP elevation and inhibition of VEGF signalling. EXPERIMENTAL APPROACHWe used conscious rats with automated blood sampling and radio telemetry and anaesthetized rats to measure cardiovascular changes. Rat isolated aorta and isolated hearts, and human resistance vessels in vitro were also used. NO production by human microvascular endothelial cells was measured with the NO-dependent probe, DAF-FM and VEGFR2 phosphorylation was determined in mouse lung, ex vivo. KEY RESULTSIn conscious rats, fostamatinib dose-dependently increased BP. The time course of the BP effect correlated closely with the plasma concentrations of R406 (the active metabolite of fostamatinib). In anaesthetized rats, infusion of R406 increased BP and decreased femoral arterial conductance. Endothelial function was unaffected, as infusion of R406 did not inhibit hyperaemia-or ACh-induced vasodilatation in rats. R406 did not affect contraction of isolated blood vessels. R406 inhibited VEGF-stimulated NO production from human endothelial cells in vitro, and treatment with R406 inhibited VEGFR2 phosphorylation in vivo. R406 inhibited VEGF-induced hypotension in anaesthetized rats. CONCLUSIONS AND IMPLICATIONSIncreased vascular resistance, secondary to reduced VEGF-induced NO release from endothelium, may contribute to BP increases observed with fostamatanib. This is consistent with the elevated BP induced by other drugs inhibiting VEGF signalling, although the contribution of other mechanisms cannot be excluded. AbbreviationsDABP, diastolic arterial BP; dP/dt +/−, the rate of left ventricle pressure rise and decline; FBF, femoral arterial blood

Quantifying the relationship between inhibition of VEGF receptor 2, drug‐induced blood pressure elevation and hypertension

“…The data presented in Figures and suggest a close alignment between the PKPD relationship for VEGFR‐2‐mediated blood pressure effect in both humans and rats. A number of other publications have also shown that VEGFR‐2‐inhibiting compounds known to cause hypertension in humans also cause blood pressure elevation in rats (Banfor et al, ; Isobe et al, ; Skinner et al, ; Carter et al, ). These data therefore suggest that the role of VEGFR‐2 in regulating blood pressure is conserved in both species.…”

Fostamatinib for Persistent/Chronic Adult Immune Thrombocytopenia

“…Off-target inhibition of VEGFR2 was found to increase vascular resistance and reduced VEGF-induced nitric oxide release in animal models [50], where effects were dose-dependent, but effectively managed by drug withdrawal or concomitant treatment with antihypertensive agents [51]. R406 also inhibited VEGF-dependent human endothelial cell tube formation and tube outgrowth, further supporting a possible role for VEGF signaling in blood pressure effects of fostamatinib [48].…”

“…In a separate kinase screen, VEGFR2 was identified as a secondary target of fostamatinib and further evaluated as a possible mechanism for the elevated blood pressure and increased incidence of hypertension previously observed in clinical studies of fostamatinib [47,50]. Off-target inhibition of VEGFR2 was found to increase vascular resistance and reduced VEGF-induced nitric oxide release in animal models [50], where effects were dose-dependent, but effectively managed by drug withdrawal or concomitant treatment with antihypertensive agents [51].…”

Spleen Tyrosine Kinase: A Crucial Player and Potential Therapeutic Target in Renal Disease

“…The effect of fostamatinib on blood pressure elevation (mean increase of ∼3 mm Hg in both systolic and diastolic) appeared to be dose dependent, and a concentration-dependent increase of blood pressure was observed with increasing R406 concentrations. Fostamatinib-induced hypertension may be attributed to increased vascular resistance, secondary to reduced vascular endothelial growth factor-induced nitric oxide release from endothelium [55]. Blood pressure usually returns to normal upon decrease in fostamatinib dose or its withdrawal.…”