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Mechanisms in Notch-mediated Development of Arteriovenous Malformation

  • Author(s): Kim, Tyson Nam
  • Advisor(s): Wang, Rong A
  • et al.
Abstract

The vasculature arborizes as an elegant system of branching arteries, veins, and capillaries. For over a century, forces exerted by blood flow have been recognized to determine the arterial and venous (AV) identities of blood vessels. Recent studies have uncovered genes that are uniquely expressed in arteries but not veins, and vice versa. It is thought that these AV markers are expressed prior to circulation and necessary for the morphogenesis of embryonic arteries and veins, suggesting an interplay of biochemical and hemodynamic cues in development and maintenance of the AV network.

The programs regulating the AV network are disrupted in arteriovenous malformation (AVM), a dangerous condition characterized by enlarged, tangled shunts between arteries and veins that bypass capillaries. These high-flow lesions are believed to persist and enlarge under the influence of blood flow, and the abnormal hemodynamic stress exerted on the vasculature can lead to life-threatening ruptures in organs such as brain. To date, the origin of AVMs is poorly understood. These lesions are speculated to persist as congenital abnormalities from embryonic development, or arise de novo later in life. We have previously reported a mouse model of AVMs, wherein endothelial expression of constitutively active Notch4, a potent regulator of arterial identity, caused high-flow shunts to directly join arteries and veins. We hypothesized that reprogramming of the endothelium caused postnatal AVMs through the enlargement of pre-existing capillaries.

We constructed a two-photon laser scanning microscope for in vivo observation of vascular development over time. We developed a method to quantify blood velocities in high-flow AVMs, enabling correlation of hemodynamics and formation of these lesions. Utilizing these tools, we discovered that brain AVMs developed from the established AV network by the enlargement of pre-existing microvessels. Additionally, we found that normalization of Notch signaling in our mouse model resulted in the regression of AVMs to capillary-like vessels. Taken together, these results suggest that AVM may arise from capillaries, and importantly, may be a reversible process. This work presents tools that will be highly useful in the study of developmental vascular biology, and sheds light on the pathogenesis of arteriovenous malformations in general.

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