N-Hydroxyarginine as a Redox Activated Nitric Oxide Therapy

Endothelial dysfunction is a unifying mechanism in diabetes, atherosclerosis and other chronic cardiovascular diseases. It is driven by oxidative stress and loss of nitric oxide (NO) bioavailability, particularly through oxidation of the essential eNOS cofactor tetrahydrobiopterin (BH4) to 7,8‑dihydrobiopterin (BH2). This “uncouples” endothelial nitric oxide synthase (eNOS), switching its output from NO to superoxide and peroxynitrite, thereby perpetuating vascular injury.

This project will investigate N‑hydroxy‑L‑arginine (NOHA), the natural intermediate in NO synthesis, as a novel redox‑activated NO therapy. Previous work in our group has shown that NOHA has a unique dual action: it reacts with reactive oxygen species to generate NO or NO‑related species while consuming oxidants, and it can serve as a substrate for BH2‑bound eNOS, effectively turning uncoupled eNOS from a pathological ROS source into a local NO generator. In endothelial cells exposed to high glucose, NOHA restores NO production, reduces oxidative and nitrosative stress, and normalises BH4 redox balance.

The PhD will first define how NOHA behaves as a ROS scavenger and NO donor in vitro and in primary human aortic endothelial cells. It will then use quantitative proteomics to map the downstream endothelial signalling pathways modulated by NOHA under hyperglycaemic and inflammatory conditions. Finally, it will assess whether NOHA can restore endothelial function in advanced in vitro models, including angiogenesis assays, monocyte adhesion and electric cell‑substrate impedance sensing (ECIS) to monitor barrier integrity and wound healing.

The project will employ a range of techniques including cell culture, quantitative NO and ROS assays, HPLC‑EC analysis of pterins, proteomics, Western blotting, angiogenesis and adhesion assays, and ECIS. The successful candidate will be co‑supervised by Dr Mark Crabtree and vascular biologist Dr Paola Campagnolo. The studentship is suitable for candidates with a strong background in biomedical sciences, pharmacology, physiology or a related discipline, and a keen interest in cardiovascular research, redox biology and endothelial signalling.

Open to candidates who pay UK/home rate fees. See UKCISA for further information.

You will need to meet the minimum entry requirements for our Biosciences and Medicine PhD.