Abstract
Heart disease, stroke, diabetes, cancer, and kidney disease are leading causes of death in the United States. Across this wide range of complex diseases, the dysfunction in hemodynamics and oxygen metabolism plays an important role. However, the mechanistic details remain incompletely understood. Exquisitely sensitive to blood hemoglobin—the primary oxygen carrier in the circulation, multi-parametric PAM holds great potential to bridge the knowledge gap. My thesis research focuses on the development of advanced multi-parametric PAM instruments and complementary analytical tools, which together have enabled comprehensive quantification of hemodynamics and oxygen metabolism at the microscopic level in vivo. I have demonstrated the utility of this first-of-a-kind hardware-software platform in multiple tissue/organ sites (e.g., the skin, brain, kidney and muscle) and have applied it to study hemodynamic and oxygen-metabolic dysfunction in multiple mouse disease models, including ligation-based hemodynamic redistribution and arteriogenesis, acute kidney injury, ischemic stroke, neonatal brain injury, wound healing, and cancer.
In Chapter 2, we developed a set of novel algorithms for CHb quantification, tissue-level MRO2 /CMRO2 quantification, vessel segmentation, the ultrasound-aided and real-time contour imaging methods. In Chapter 3, we revealed a new, inverse relationship between initial vascular resistance and extent of arteriogenesis, as well as the moderate diameter increase and flow upregulation in collateral arterioles for obese mice which were subsequently lost compared to the lean mice, after the ligation of feeding arteries. In Chapter 4, we showed that intradermal injection of AZD8601 formulated in a biocompatible vehicle results in pronounced, sustained and dose-dependent vasodilation, blood flow upregulation, and neovessel formation, in striking contrast to those induced by recombinant human VEGF-A protein, a non-translatable variant of AZD8601, and citrate/saline vehicle. And we also showed that sequential dosing of AZD8601 could accelerated re-epithelialization during the early phase of diabetic wound healing. In Chapter 5, we revealed a strong correlation between inhaled oxygen concentration and measured sO2 of mouse kidney, and the change of oxygen stress was associated with reduced kidney ATP levels in the early stages of LPS-induced AKI. In Chapter 6, a first-of-a-kind long-lifetime (>5 months), cortex-wide (6×8 mm2), and light-weight (<2 g) cranial window approach was explored, and utilized in awake versus. anesthesia comparison and longitudinally monitoring the cerebrovascular responses to photothrombotic stroke throughout the recovery process. In Chapter 7, we utilized the multi-parametric PAM in neonatal mice using the Vannucci HI model and the results showed a rapid drop of CMRO2 during the HI with rapid recovery in the latent phase, and finally irreversible dropped again as the second energy failure. The effectiveness of therapeutic hypothermia was also confirmed by the hypothermia reduced post-HI mitochondrial hyperactivity and moderate decrease of CMRO2.
