Header image

Keynote Address: BPS Lecturer I Prof Jeanette Woolard

Wednesday, December 10, 2025
8:00 AM - 8:50 AM
Hall C Lower Section

Details

Vascular Endothelial Growth Factor (VEGF) is a key signalling molecule in angiogenesis. One of its three receptors, VEGFR-2, has been shown to be the dominant mediator of VEGF-A-induced cellular responses involved in the formation of new vasculature to support cancer growth [1]. Most human tumours overexpress VEGF messenger ribonucleic acid (mRNA), and many tumour cell lines have an increased expression of these receptors, emphasizing the crucial role of VEGF as a mediator in tumour angiogenesis. To inhibit angiogenesis in cancer, a number of therapeutic agents that interfere with VEGF signalling have been developed. These include small molecule receptor tyrosine kinase inhibitors (RTKIs) that target the intracellular adenosine triphosphate (ATP)-binding site of the VEGFR-2 kinase [2]. Hypertension is one of the most common complications reported in cancer patients treated with RTKIs such as axitinib, lenvatinib and sorafenib [3]. However, the mechanisms underlying these effects remain to be established. One proposed mechanism involves the endothelin-1 (ET-1) axis. ET-1 is a potent vasoconstrictor peptide, whose biological activity is mediated by its binding to two G protein-coupled receptors, ETA (endothelin receptor type A) and ETB (endothelin receptor type B), which are both expressed on vascular smooth muscle cells. We have therefore used the selective ETA antagonist, sitaxentan, and the non-selective ETA/ETB antagonist, bosentan, to investigate their effect on VEGFR-2 signalling and cardiovascular haemodynamics induced by two of the most potent VEGFR-2 inhibitors, axitinib and lenvantinib, in conscious, freely-moving rats [4]. These studies confirmed that two potent inhibitors of VEGFR-2-signalling (axitinib and lenvatinib) can induce a significant increase in mean arterial pressure that is accompanied by significant vasoconstriction within the mesenteric and hindquarters vascular beds. Data obtained with ET-1 receptor antagonists, however, show that the hypertensive response to both axitinib and lenvatinib can be prevented by selective ETA antagonism [4]. Taken together, these results indicate that treatment of patients with selective ETA antagonists might prevent the development of the drug-induced hypertension that is a common side effect of both axitinib and lenvatinib. [1] C.J. Peach et al (2018) Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2. Int J Mol Sci. 19, 1264. [2] M. Van Daele et al (2023). Characterisation of tyrosine kinase inhibitor-receptor interactions at VEGFR2 using sunitinib-red and nanoBRET. Biochem Pharmacol. 214, 115672. [3] J.J. Carter et al (2017). Effects of 4 multitargeted receptor tyrosine kinase inhibitors on regional hemodynamics in conscious, freely moving rats. FASEB J. 31, 1193-1203. [4] P. Pannucci (2024) Role of endothelin ETA receptors in the hypertension induced by the VEGFR-2 kinase inhibitors axitinib and lenvatinib in conscious freely-moving rats. Biochem Pharmacol. 228:116007.


Speaker

Agenda Item Image
Prof Jeanette Woolard Isaac
University of Nottingham

Role of Endothelial Receptors in the Hypertension Induced by VEGFR-2 Inhibitors

Biography

Prof Woolard Isaac leads one of the few laboratories in the world capable of monitoring complex cardiovascular responses in conscious animals. Her in vivo laboratory is internationally recognised for its unique capability to measure regional blood flow across three distinct vascular beds in conscious subjects. This expertise has enabled her to secure major external research grants and foster impactful collaborations with industry partners including AstraZeneca, Promega, Heptares, and Medicines Discovery Catapult. She has also established major international research collaborations with teams across Europe, the USA, and Australia. She is a co-applicant on a £2 million MRC programme grant and serves as Principal Investigator on a recently awarded £4.5 million Wellcome Trust four-year PhD programme in Drug Discovery and Team Science. Additionally, she is the Nottingham lead on a €3.8 million European Commission-funded Marie Skłodowska-Curie Actions ITN INSPIRE project (INnovation in Safety Pharmacology for Integrated cardiovascular safety assessment to REduce adverse events and late-stage drug attrition). Since January 2021, she has served as the Nottingham Director of the £10 million Centre of Membrane Proteins and Receptors (COMPARE), following her role as Deputy Director since the Centre’s inception. In 2020, she was awarded a Fellowship by the British Pharmacological Society and received the Vice-Chancellor’s Medal from the University of Nottingham in recognition of her contributions to Team Science. More recently, she was honoured with the BPS/AstraZeneca EDI Prize for her continued leadership in research culture development. Her research has led to highly cited publications in the areas of cancer and angiogenesis, with recent high-impact papers published in Cell Chemical Biology, Communications Biology, FASEB Journal, British Journal of Pharmacology, and Biochemical Pharmacology. Her work focuses on elucidating the molecular pharmacology of vascular endothelial growth factor (VEGF-A) isoforms and VEGFR2 receptors. She has contributed to the development of fluorescent ligands to study VEGFR2 (in collaboration with Promega), and has applied NanoBRET approaches to monitor GPCR target engagement in tumours in vivo (in partnership with Monash University). Her laboratory continues to explore the mechanisms underlying the hypertensive effects of receptor tyrosine kinase inhibitors, particularly those targeting VEGF pathways. In September 2024, she assumed the role of Associate Pro-Vice-Chancellor for the Research Academy and Research Culture Development. As a member of the University of Nottingham’s senior strategic leadership team, she is focused on enhancing student engagement, experience, and learning. Her aim is to ensure the University remains at the forefront of research and teaching excellence, particularly at the postgraduate level. Central to this is her commitment to supporting supervisory teams, fostering an exceptional research environment, and ensuring the student voice is valued and aligned with the University’s strategic priorities.

Chair

Agenda Item Image
Bridin Murnion
Senior Staff Specialist
St Vincent's Hospital / UNSW Sydney

loading