Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by a multi-systemic vascular dysplasia and hemorrhage. The precise factors leading to these vascular malformations are not yet understood and robust animal models of HHT are essential to gain a detailed understanding of the molecular and cellular events that lead to clinical symptoms, as well as to test new therapeutic modalities. Most cases of HHT are caused by mutations in either endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1, also known as ALK1). Both genes are associated with TGFβ/BMP signaling, and loss of function mutations in the co-receptor ENG are causal in HHT1, while HHT2 is associated with mutations in the signaling receptor ACVRL1. Significant advances in mouse genetics have provided powerful ways to study the function of Eng and Acvrl1 in vivo, and to generate mouse models of HHT disease. Mice that are null for either Acvrl1 or Eng genes show embryonic lethality due to major defects in angiogenesis and heart development. However mice that are heterozygous for mutations in either of these genes develop to adulthood with no effect on survival. Although these heterozygous mice exhibit selected vascular phenotypes relevant to the clinical pathology of HHT, the phenotypes are variable and generally quite mild. An alternative approach using conditional knockout mice allows us to study the effects of specific inactivation of either Eng or Acvrl1 at different times in development and in different cell types. These conditional knockout mice provide robust and reproducible models of arteriovenous malformations, and they are currently being used to unravel the causal factors in HHT pathologies. In this review, we will summarize the strengths and limitations of current mouse models of HHT, discuss how knowledge obtained from these studies has already informed clinical care and explore the potential of these models for developing improved treatments for HHT patients in the future.

A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10

“…Based on the loss-of-function mutation paradigm in HHT, heterozygous KO mice for Acvrl1 or Eng were expected to exemplify the most representative models for this disease. However, Acvrl1 +/− and Eng +/− mice only displayed mild phenotypes with variable HHT-like vascular defects from one genetic background to another29. More recently, powerful inducible conditional KO mice for Acvrl1 or Eng were generated354243.…”

“…Indeed, transfection experiments showed that HHT mutations in either ALK1 or endoglin blocked activation of Smad1/5/8 signaling by BMP9262728. The notion that HHT is caused by loss-of-function mutations was strengthened by studies in mouse29 and zebrafish30 models showing that ALK1 or endoglin deficiency, or injection of ALK1 extracellular domain-derived ligand trap (ALK1-Fc), led to vascular hyperproliferation and AVMs. It is important to note that AVMs in some of these models were consistently and robustly observed when ALK1 or endoglin was completely deleted or inhibited, and when precipitating events were in place, such as angiogenesis or inflammation, a process referred to as the double or multiple hit hypothesis2931.…”

“…The notion that HHT is caused by loss-of-function mutations was strengthened by studies in mouse29 and zebrafish30 models showing that ALK1 or endoglin deficiency, or injection of ALK1 extracellular domain-derived ligand trap (ALK1-Fc), led to vascular hyperproliferation and AVMs. It is important to note that AVMs in some of these models were consistently and robustly observed when ALK1 or endoglin was completely deleted or inhibited, and when precipitating events were in place, such as angiogenesis or inflammation, a process referred to as the double or multiple hit hypothesis2931. Consistent with these observations, simultaneous neutralization of BMP9 and BMP10 in the postnatal retinal angiogenesis model [by injection of anti-BMP10 antibodies (Abs) into BMP9 knockout (KO) mice, or by co-injection of anti-BMP9 and anti-BMP10 Abs into wild type mice] led to hypervascularization1718, a vascular defect that was also observed in Acvrl1 or Eng conditional KO models and thus is reminiscent of HHT pathology29.…”

The role of endoglin in post-ischemic revascularization

“…It is characterized by an impaired angiogenic process that leads to arteriovenous malformations (AVMs), fragile vessel walls, and pulmonary, liver and cerebrovascular problems due to vascular defects [122,123]. Endoglin itself is responsible for endothelium integrity because an induced lack of endoglin leads to the apparition of AVMs when a pro-angiogenic or an inflammatory stimulus occurs in mice with endothelial-specific loss of endoglin (Eng-iKO e ) [124,125]. Moreover, recent evidence has demonstrated that endoglin deficiency inhibits shear fluid stress blockage of EC proliferation together with pericyte recruitment [76].…”

Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure

“…Global inducible knockout of Alk1 in adult mice results in lethality associated with the formation of arteriovenous malformations in the gastrointestinal tract and subsequent development of high output HF[8, 9]. For this reason, several studies have employed the Alk1 heterozygous mouse model to study the post-natal effects of ALK1 deficiency [6, 10, 11]. …”