Inhibition of angiogenesis, by targeting VEGF signaling, has revolutionized cancer therapy with improved outcomes in some previously untreatable cancers. However, clinical observations unexpectedly showed that VEGF inhibition (VEGFI) was associated with cardiovascular toxicity, especially hypertension. Molecular mechanisms underlying VEGFI induced hypertension are unclear, but endothelial dysfunction, oxidative stress have been implicated. In particular, oxidative stress is one of the major mediators of vascular inflammation that is particularly relevant for vascular remodeling and development of hypertension. Among the different sources of reactive oxygen species (ROS) mitochondria (mt) appear relevant particularly in chronic diseases and ageing, since mtROS through induction of the intracellular superoxide anions represents an emerging mechanism of inflammatory response, possibly involved in vascular and cellular aging. One of the major regulator of mtROS is p66Shc which has classically been implicated in cellular responses to oxidative stress and redox-sensitive processes associated with ageing and longevity. Recent evidences have shown that beyond its effects on vascular wall remodeling, p66Shc can be associate to VEGF receptor signaling. The aim of our study is to investigate mechanisms involved in the development of hypertension and microvascular damage during antiangiogenic treatment with VEGFI. We will focus on mitochondrial oxidative stress, in particular on the role of p66Shc which may be involved in the generation of reactive oxygen species by the mitochondria, and thus in the development of inflammatory responses and microvascular damage and therefore might be in part responsible of the development of microvascular dysfunction during the antagonism of VEGF.
Expected results
Findings from our study will demonstrate that VEGF inhibition may induce hypertension, which is associated with vascular inflammation and increased phosphorylation of p66Shc and activation of pro-inflammatory pathways.
This may further underlines the importance of VEGF inhibiotn in ROS production and vascular inflammation.
In p66Shc K/O mice VEGF receptor phosphorilation/activation could be downregulated, with associated decrease in vascular inflammation and remodeling.
Significance.
Our in vivo study will advance the field of VEGF-receptor biology and VEGF inhibition and will identify a new downstream pro-inflammatory signaling pathway through p66Shc.
Moreover, we will define inflammation as a new biological response of p66Shc, particularly during VEGF inhibition.
Considering the growing interest in p66Shc inhibitors as a therapeutic strategy our findings may suggest a novel approach in treating vascular alteration associated with VEGF inhibition.