KAI1/CD82 on mural cell suppresses angiogenesis by keeping vessel quiescent

Abstract

Blood vessel is a critical organ, spread all over the body for survival of every other organ. The key process forming network of those vessels is called angiogenesis. In healthy adult, angiogenesis is physiologically well-controlled by interacting between two components of vascular cell (endothelial cell and mural cell). However, in disease such as cancers or retinopathies, aberrant angiogenesis occurs out of control and becomes one of the critical factors worsening disease prognosis. As a strategy to block those pathological angiogenesis, endothelial cell has been generally targeted as an anti-angiogenic drug. However, several studies reported the clinical cases of cancer patients resistant to them. Recently, because of those obstacles, mural cell has been emerged as a new target of anti-angiogenic drug. In addition to that, it is still elusive that how interaction between endothelial cell and mural cell regulates angiogenesis to keep quiescent state at the molecular level. Here, we discovered that one of the tetraspanins, KAI1, on mural cell is a new distinct suppressor of angiogenesis in quiescent niche. From the developmental stage to the adult, Kai1-/- mice showed better angiogenic ability than wild type (WT) mice in vivo and in vitro. Furthermore, even though KAI1 molecules expressed both on endothelial cells and mural cells, majority of them were on the mural cell and only mural KAI1 played a role as a functional angiogenic suppressor. We also figured out that KAI1 on mural cell is involved in signaling transduction for anti-angiogenic effect in quiescent niche, by up-regulating and secreting LIF, which is an anti-angiogenic soluble factor, via SRC-p38/Akt pathway. We expect that this finding could contribute to establish a new axis of anti-angiogenesis in academic and clinical field.