Longer-term effects of the tissue response to hypoxia include changes in the vasculature that help restore normal delivery of oxygen to the cells and tissues. For example, HIF regulates the process of angiogenesis, or the formation of new blood vessels that provide cells and tissues with oxygen and nutrients. FibroGen is exploring the use of certain HIF stabilizing agents in disease areas where stimulation of pathways, such as angiogenesis, could provide therapeutic benefit including non-healing ulcers and pulmonary hypoplasia.

Longer time to wound closure predisposes diabetic patients to local infection, which in turn has a negative effect on healing that is mediated through inflammatory cytokines like TNF-alpha. This vicious cycle leads to persistence of the initial inflammatory phase of normal wound healing and prevention of the formation of granulation tissue, a highly vascularized, cellular tissue that provides the template for re-epithelialization (wound closure) and the subsequent deposition of extracellular matrix (mostly collagen) that provides the mechanical strength of the new tissue.

FibroGen's scientists have shown that therapeutic HIF stabilization leads to responses that will positively affect the wound healing process including the promotion of angiogenic factors, such as VEGF, and the suppression of inflammatory effects of cytokines, such as TNF-alpha. Other research published in the scientific literature also demonstrates the importance of a HIF-coordinated angiogenic response in effecting the proper formation of blood vessels without the leakiness or inflammation observed when a single agent, such as VEGF, is used. This result was advanced by showing that mice engineered to express stable HIF in the skin had a more rapid wound healing response than their non-transgenic counterparts. These studies suggest that local application of HIF stabilizing agents to chronic non-healing wounds can stimulate the formation of granulation tissue and promote proper wound healing.

HIF-mediated angiogenesis may also have therapeutic application in pulmonary hypoplasia, a serious condition in children who are delivered pre-term. The embryonic period constitutes a period of constant hypoxia. Stable HIF protein can be detected in embryonic tissues until the very last day of pregnancy. HIF-1 is an extremely important factor for morphogenesis and ensures the proper development of the cardiovascular system. In children who are delivered pre-term, sudden exposure of the immature lung to atmospheric oxygen levels leads to a rapid degradation of HIF and an arrest of lung maturation, contributing to the well-known pulmonary problems in these children. The potential use of FibroGen HIF stabilizing agents for treating pulmonary hypoplasia is being studied with collaborators at the National Jewish Research Center in Denver, Colorado.