Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia

PROJECT SUMMARY Therapeutic advances in vascular disease may have far-reaching public benefits. Arteriovenous malformations (AVMs) are the common feature of hereditary hemorrhagic telangiectasia (HHT) and cause the high risk of life- threatening complications. Advanced studies have shown that loss function of mutations in activin receptor-like kinase 1 (ALK1) are linked to HHT type 2 (HHT2) and ALK1 gene deletion in mice causes AVMs. Previous studies also reveal that ALK1 is predominantly expressed in arterial endothelial cells (ECs). However, it is unknown if ALK1 deficiency allows arterial ECs to acquire ill characteristics resulting in AVMs. In present proposal, we have obtained preliminary data to suggest that the emerging lymphatic endothelial characteristics in arterial ECs through the induction of mouse double minute 2 (MDM2) is previously unknown mechanism of AVMs in endothelial ALK1 deficiency, and we show that the approaches of erasing these undesired characteristics reduce AVMs. Therefore, we hypothesize that ALK1 deficiency elevates MDM2 to cause AVMs through the induction of lymphatic endothelial characteristics in arterial ECs, and MDM2 inhibition abolishes these characteristics to reduce AVMs. In specific Aim 1, we will elucidate the mechanism underlying arterial MDM2 induction as a causative factor of AVMs in endothelial ALK1 deficiency. In specific Aim 2, we will determine the contribution of arterial MDM2 induction to human HHT2. In specific Aim 3, we will determine if limiting MDM2 reduces AVMs in endothelial ALK1-deficient mice. There is no primary medical treatment to prevent or reduce the AVMs of HHT2 patients. In this proposal, we discover a novel mechanism that reveals the unwanted characteristics emerging in arterial ECs driven by ALK1 deficiency, and arterial ECs with these characteristics cause AVMs. We identify a compound and propose a novel treatment paradigm aiming to ameliorate AVMs by erasing these ill characteristics from arterial ECs. If succussed, our proposed studies would reveal the mechanistic underpinnings of alterations in arterial ECs of HHT2 and provide insight into new opportunities for therapeutic interventions.