Angiogenesis, the growth of new blood vessels from pre-existing vessels, is a complex and dynamic process that is essential for proper development. During adulthood, the majority of vessels are quiescent, with angiogenesis being restricted to regenerative tissues, such as the uterine lining and healing wounds. The wound healing response mimics the early stages of tumorigenesis in many ways, including the formation of tortuous vessels. However, a significant difference is that tortuous vessels in a wound environment resolve after the wound is healed, whereas cancer vessels maintain their tortuosity. In contrast, a non-cancer pathological model of oxygen-induced retinopathy (OIR) is characterized by tortuous vessels that also eventually resolve. By understanding the process of tortuous vessel formation in environments that are similar to cancer but able to resolve, we can begin to dissect novel therapeutic targets towards normalization of the tumor microvasculature. Studies of angiogenesis during wound healing have increased in the past decade; however, high resolution analysis in vivo is lacking. Using multi-photon microscopy, we visualized wound healing-associated angiogenesis in vivo with an ear biopsy punch model in a vascular reporter line. This new technique has allowed us to capture the spatiotemporal dynamics of tortuous vessel formation and sprouting during wound healing. Preliminary analysis of vessel dynamics during wound healing show that vessels surrounding a wound become tortuous, displaying oscillations or kinks, and then normalize once the wound is healed. Further examination of tortuous vessels shows that these vessels display sprouting events at a higher frequency than normal vessels. This novel finding suggests that tortuous vessels may be an important intermediate step during wound healing, increasing blood vessel growth and nutrient uptake near the wound site, and subsequently stabilizing when nutrients are no longer needed. Due to these observations, we hypothesize that tortuous vessels harbor more dynamic endothelial cells, and that these differential dynamics contribute to tortuous vessel formation and sprouting. We are also examining the effects of the bone morphogenetic protein (BMP) pathway on tortuous vessel formation and sprouting. Studies from our lab and others have shown that exogenous BMPs can promote blood vessel spouting, branching, and migration in the developing retina. In this respect, we suggest that manipulation of the BMP pathway, through loss of function, will decrease endothelial cell dynamics in tortuous vessels of wounds and in OIR, affecting their formation and sprouting. To address this, we will use an inducible, endothelial-specific, conditional knock-out of BMP receptor 2 to monitor in vivo tortuous vessel formation and sprouting during wound healing and OIR. The results from these studies will provide the first characterization of endothelial cell sprouting from tortuous vessels during pathological/physiological angiogenesis and identify the role of the BMP pathway in modulating this event.
Tortuous vessels during wound healing and cancer are both abnormal, however a significant difference is that tortuous vessels in a wound environment become normal after the wound is healed, whereas cancer tortuous vessels maintain their tortuosity, which aids tumor metastasis. By understanding the process of tortuous vessel formation in environments that are similar to cancer, but with resolution of tortuosity, we can begin to identify therapeutic targets towards normalization of the tumor microvasculature. The purpose of my proposal is to examine the fundamental differences between tortuous and normal vessels and determine the role of a genetic component involved in this process.
| Chong, Diana C; Yu, Zhixian; Brighton, Hailey E et al. (2017) Tortuous Microvessels Contribute to Wound Healing via Sprouting Angiogenesis. Arterioscler Thromb Vasc Biol 37:1903-1912 |
