Identification of Risk Factors for AVM Formation in HHT



Treatment of Disease: $50,000 Research Grant

Douglas Marchuk, Ph.D.
Duke University



Although mutations in one of two genes, endoglin and ACVRL1, cause HHT, questions pertaining to vascular lesion formation in HHT remain largely unanswered. These vascular lesions in HHT develop in discrete locations, and often increase in number and size with age. The focal nature of these lesions and their age-dependent appearance suggests that yet undiscovered “factors” initiate lesion development. The identification of these initiation factors could lead to new approaches and therapies to reduce the incidence of vascular lesion formation.

According to Dr. Marchuk, “My laboratory has recently shown that older mice heterozygous for an engineered acvrl1 mutation show many features of the human HHT phenotype. Using a genetic approach, we will cross the ACVRL1 mutation into various genetic backgrounds that will enable us to test specific hypotheses concerning the nature of the initiation factor(s) for lesion formation. These genetically sensitized backgrounds are mutant mice that exhibit various potential physiological triggers for lesion formation, including (1) local alterations in blood pressure, (2) hypoxia of the surrounding tissue, (3) local inflammation of the endothelium, or (4) a second somatic mutation in the wild-type copy of the gene.”

One (or more) of these sensitized genetic backgrounds may show an increase in AVM formation, lending further support for that particular trigger for lesion formation. Some of these physiological triggers can be reduced by currently-available pharmacological treatments, lending some hope of a long-term treatment outcome from this work. In addition, this work may lead to a more highly-penetrant animal model for HHT for further investigation into the mechanisms of HHT pathogenesis.


Research Study Update

Despite the discoveries of the HHT genes, many questions remain unanswered concerning the role of these genes in the pathogenesis of HHT. The most critical question is an explanation for the focal nature of the vascular lesions associated with this disorder. Germline mutations only predispose the individual to the development of the discrete focal vascular lesions. The aim of our proposal was to identify the “trigger(s)” for vascular lesion development.

Various hypotheses have been proposed to explain the actual trigger for lesion development. These include:

  1. Elevated Blood Pressure (cross with Agt tg and eNos null mice)
  2. Tissue Hypoxia (cross with Csf2 and EpoR null mice)
  3. Local Inflammation (cross with IL2 and IL10 null mice) d. Loss of Heterozygosity at Acvrl1 (Cross with p53 null and Blm hypomorph mice)

According to Dr. Marchuk, “We did not find that loss of eNos, IL10, or p53 greatly exacerbated the phenotype of HHT mice. But we can say with some confidence that in the existing HHT mouse models, these various triggers do not appear to be the limiting factor in causing the HHT lesions. After performing the initial crosses to create the appropriate mutant mice, we began aging the mice. Here again we chose the 6 month end point to examine the mice. This final cross is ongoing and we have thus far analyzed only 9 of the double mutant mice. However, we are cautiously excited about our initial results with this cross. In about 1/3 of the mutant mice, we have found grossly dilated vessels on the surface of the liver. We have seen this level of dilation occasionally before, but we have never routinely seen this phenotype in HHT mice at such an early age.”


Dr. Marchuk’s team is deeply grateful for this funding from Cure HHT which made their work possible. “We hope sometime in the future to leverage your investment in our work with a funded NIH grant proposal to continue our work on identifying the trigger for vascular lesion formation in HHT.”