Regression of pathological blood vessels by inhibition of mast cell function

Abstract

1. Mast cells align with established pathological blood vessels. 2. Mast cells enhance vessel stability and prolong their persistence through secretion of angiopoietin-1. Angiogenic pathologies, such as cancers, autoimmune disorders, and ocular diseases, are characterized by the presence of both new and established blood vessels. Current antiangiogenic treatments primarily target newly formed vessels, leaving established ones largely unaffected. However, mechanisms underlying the stability of these mature vessels in angiogenic pathologies remain poorly understood. Here, we demonstrate that mast cells (MCs), aligned alongside established pathological vessels, promote vessel stability and delay their regression via angiopoietin-1 (Angpt1). In a murine model of suture-induced corneal angiogenesis to establish mature blood vessels, we demonstrate that following suture removal, vessel regression is significantly accelerated in MC-deficient cKit w-sh mice and upon pharmacological inhibition of MC function with cromolyn in wild-type mice. Further, in vitro co-culture experiments with MCs and vascular endothelial cells show that MCs help preserve the stability of tube networks, which is lost following cromolyn treatment or Angpt1 neutralization. Finally, adoptive transfer of Angpt1 -silenced MCs in cKit w-sh mice subconjunctivally results in significantly faster regression of pre-existing blood vessels, whereas transfer of mock-silenced MCs does not. Our findings suggest that MCs, via Angpt1 expression, play a crucial role in stabilizing pathological blood vessels, offering potential targets for therapeutic intervention in angiogenic disorders.