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Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Dr. J Geoffrey Pickering

Abstract

Angiogenesis is the process of generating new blood microvessels. In adults, angiogenesis is fundamental to tumor biology and also to tissues rendered ischemic from vascular occlusion. Despite a promising appeal, strategies designed to simulate or otherwise modify the angiogenic process in adult tissues have yet to realize significant therapeutic potential. Importantly, understanding the structure and function of new microvascular networks formed in adult, diseased tissues is limited. In fact, it remains unknown if a new or regenerated microcirculation can effectively deliver oxygen to the tissue. The purpose of this thesis was to seek out novel determinants of functional angiogenesis and microvascular regeneration.

Using a novel real-time microscopy strategy for imaging red blood cells (RBCs), I interrogated microcirculatory architecture and perfusion in mouse renal cell carcinomas. I found that the tumor microvasculature was devoid of hierarchy, microvessel specification, and vasoreactivity. Furthermore, I found that fibroblast growth factor 9 can productively reconfigure the tumor microvasculature into a hierarchical network of arteriole-capillary-venular units, with vasomotor competence. Together, these findings revealed important microvascular abnormalities in tumors and established that attainment of a physiologically advanced microcirculation in tumors is achievable.

I next interrogated the structure and function of the regenerated microvasculature that forms in skeletal muscle following ischemic injury. I discovered that despite extensive angiogenesis, there are profound flaws in microvascular network geometry, hierarchy, RBC transit, flow control by hypoxia, and smooth muscle cell wrapping around arterioles. Thus, the neo-microvasculature in regenerated skeletal muscle does not recapitulate the anatomy and physiology of a normal microvasculature and is ineffective at controlling the delivery of oxygen.

In summary, this thesis provides novel insights into adult angiogenesis and the workings of microvascular systems that have been injured by disease. These findings have relevance to strategies for restoring oxygen content in pathological tissues.

Summary for Lay Audience

Angiogenesis is the process of generating new blood microvessels. In adults, angiogenesis is fundamental to tumor biology and also to tissues rendered ischemic from vascular occlusion. Despite a promising appeal, strategies designed to simulate or otherwise modify the angiogenic process in adult tissues have yet to realize significant therapeutic potential. Importantly, understanding the structure and function of new microvascular networks formed in adult, diseased tissues is limited. In fact, it remains unknown if a new or regenerated microcirculation can effectively deliver oxygen to the tissue. The purpose of this thesis was to seek out novel determinants of functional angiogenesis and microvascular regeneration.

Using a novel real-time microscopy strategy for imaging red blood cells (RBCs), I interrogated microcirculatory architecture and perfusion in mouse renal cell carcinomas. I found that the tumor microvasculature was devoid of hierarchy, microvessel specification, and vasoreactivity. Furthermore, I found that fibroblast growth factor 9 can productively reconfigure the tumor microvasculature into a hierarchical network of arteriole-capillary-venular units, with vasomotor competence. Together, these findings revealed important microvascular abnormalities in tumors and established that attainment of a physiologically advanced microcirculation in tumors is achievable.

I next interrogated the structure and function of the regenerated microvasculature that forms in skeletal muscle following ischemic injury. I discovered that despite extensive angiogenesis, there are profound flaws in microvascular network geometry, hierarchy, RBC transit, flow control by hypoxia, and smooth muscle cell wrapping around arterioles. Thus, the neo-microvasculature in regenerated skeletal muscle does not recapitulate the anatomy and physiology of a normal microvasculature and is ineffective at controlling the delivery of oxygen.

In summary, this thesis provides novel insights into adult angiogenesis and the workings of microvascular systems that have been injured by disease. These findings have relevance to strategies for restoring oxygen content in pathological tissues.

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