Arteriovenous malformations (AVMs) are dangerous vascular lesions of largely unknown etiology. Those that occur in the brain (BAVMs) are particularly devastating, since they often lead to hemorrhagic stroke. Current treatment strategies are limited and may be as risky as the disease itself. At their core, AVMs are an aberration of normal vascular hierarchy caused by enlarged direct connections between the artery and the vein, which shunt blood past the capillary bed. Influenced by the discovery of a Notch-regulated program of arteriovenous (AV) specification, I hypothesized that disruption of this program could cause BAVM. My thesis work identifies increased endothelial Notch signaling as a candidate lesion in brain AVMs by showing that it is sufficient to cause BAVM-like abnormalities in a mouse model, and that it is upregulated in human BAVM tissue samples. Furthermore, it demonstrates that a sustained increase in Notch signaling is required to maintain the BAVMs in our mouse model, since high-flow AVMs rapidly regress to capillaries once Notch transgene is turned off. This work will be presented as three chapters, the first two of which have been published (PMID: 18667694 and PMID: 19546852), and the third of which is submitted for publication.

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.

A functional brain vascular supply is crucial for delivery of life-essential nutrients and removal of metabolites. Abnormal vascular development and hemodynamics can result in pathologies of many vascular diseases. The enlarged high-flow blood vessels that shunt blood from arteries to veins can cause arteriovenous malformation (AVM) and it can lead to life-threatening ruptures in the brain. The ability to correlate the relationship between blood flow with vascular structure at cell levels in living animals would foster our knowledge of the disease. Conventional wide-field microscopy is powerful in imaging at cell levels; however, light penetration depth is the limitation in deep tissue imaging. Near-infrared fluorescence imaging system can achieve deep tissue imaging but the low spatial resolution makes it difficult to map vascular structure and blood flow. In this research, we use two-photon laser scanning microscopy that can achieve deep tissue imaging and high spatial resolution to do cerebral vascular imaging in the genetic mutant mice that showing the phenotype of AVM. By using the line-scan imaging and 3D scan, we are able to analyze the blood velocity and diameter of the blood vessel that give the dynamic information of blood flow and vascular structure. We hope the findings through “5D” two-photon microscopy imaging that include high spatial vascular structure (3D) and blood velocity (4th dimension) over a period of time (5th dimension) can improve insights for the mechanism of AVM formation in the brain.

A novel ballast resistor network is proposed to achieve a better thermal management in HBT power cells without degrading the RF performances. Experiments were conducted on two HBT power amplifiers. They occupy same area. One is designed using conventional ballast network. The other uses proposed novel network. Temperature comparisons were made based on the same current density. Infrared camera images show that a more uniform temperature distribution is obtained in novel ballast network power amplifier. Our results demonstrate that the proposed novel ballast network has promising applications in high power amplifiers. (C) 2008 Wiley Periodicals, Inc.

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