Role of Bone Morphogenic Protein (BMP) signaling in Arterial-Venous Malformation (AVM)

Fluid shear stress (FSS), a mechanical force induced upon blood flow and circulating soluble factors regulate the formation, remodeling, and maturation of the vasculature. Among those, Bone morphogenic protein 9 (BMP9) and BMP10 proteins, along with physiological FSS, promote and maintain vascular homeostasis. Heterozygous loss of function (LOF) mutations in the BMP9/10 receptors: activin like kinase 1 (ACVRL1 encoding ALK1), ENG encoding Endoglin, or the downstream transcriptional effector, Mothers Against Decapentaplegic Homolog 4 (MADH4 encoding SMAD4, leads to Hereditary Haemorrhagic Telangiectasia (HHT) vascular disorder, which is characterized by the formation of fragile and leaky telangiectasis and large arterial venous malformations (AVMs). Yet, what is the exact contribution of FSS in AVM pathogenesis remains largely unclear. Based on the hypothesis that AVMs are a result of loss of FSS-mediated EC quiescence responses, my PhD studies aimed to understand the mechanistic crosstalk between FSS and SMAD signaling in physiological conditions and how disruption of this mechanism leads to AVM formation. Using in vitro and murine models of HHT, I identified that endothelial cells (ECs) upon loss of Smad4 increases the sensitivity of the ECs to FSS, resulting in a permanent and chronic remodelling, and AVM formation. Mechanistically, loss of Smad4 leads to overactivation of the FSS-induced excessive Krüppel like factor 4 (KLF4) expression that through transcriptional regulation of TEK tyrosine kinase (TEK encoding for TIE2). drives excessive activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in ECs. Disruption of physiological fluid shear stress (P-FSS)-induced cell cycle arrest in G1 due to excessive KLF4-mediated inhibition of cyclin-dependent kinase (CDK) inhibitors, resulting in loss of the arterial identity’ maintenance is the critical aberrant cell event triggering AVM formation. Even though, this study does not pinpoint the exact mechanism by which the ECs sense the FSS upstream of KLF4, nor the exact CDK inhibitors that intermediate FSS mediated cell cycle arrest, yet it provides a new mechano-transduction axis: KLF4-TIE2-PI3K/Akt-CDKs-arterial identity indispensable for protecting the endothelium against AVMs. Furthermore, this study raises the opportunities for targeting this signaling axis for therapeutic purposes in patients with HHT.