The doctoral dissertation in the field of Molecular Medicine will be examined at the Faculty of Health Sciences at Kuopio Campus.
What is the topic of your doctoral research? Why is it important to study the topic?
My doctoral research investigates how VEGF-B (Vascular Endothelial Growth Factor B), particularly its VEGF-B186 form, regulates blood vessel growth and stress responses in the heart. I studied how this protein promotes new blood vessel formation in cardiac tissue and helps heart cells adapt to metabolic and cellular stress.
This research is important because heart disease remains the leading cause of death worldwide. In conditions such as coronary artery disease and heart failure, reduced blood flow limits oxygen supply to the heart muscle. Therapeutic angiogenesis, which aims to stimulate new blood vessel growth, is a promising treatment strategy. However, previous therapies using other growth factors often caused harmful side effects such as vascular leakage and inflammation. My work aims to identify safer and more precise therapeutic approaches to improve cardiac blood supply and protect the heart.
What are the key findings or observations of your doctoral research?
I discovered that VEGF-B functions through previously unknown non-canonical mechanisms. While VEGF family proteins were traditionally thought to signal only through receptors on the cell surface, I found that full-length VEGF-B186 can enter heart cells through αvβ1 integrins and travel into the nucleus, where it directly interacts with chromatin and regulates gene activity. This is the first evidence that a VEGF family member can function as a direct nuclear gene regulator.
I also demonstrated that VEGF-B186-induced angiogenesis occurs independently of the classical VEGF receptors and instead depends on RGD-binding integrins. Inside the cell, VEGF-B activates stress-adaptive signaling pathways, particularly the IRE1α–XBP1 branch of the endoplasmic reticulum stress response, which promotes production of pro-angiogenic cytokines and endothelial progenitor cell mobilisation.
In addition, I showed that a modified cleavage-resistant form, VEGF-B186R127S, promotes blood vessel growth in the heart without the dangerous arrhythmias associated with the native protein, making it a promising therapeutic candidate.
Together, these findings fundamentally change our understanding of VEGF-B biology and may support the development of safer therapeutic angiogenesis strategies for ischemic heart disease and heart failure.
How can the results of your doctoral research be utilised in practice?
The findings of my doctoral research may help develop new gene therapy and regenerative medicine approaches for ischemic heart disease and heart failure. By identifying new receptors and intracellular signaling mechanisms of VEGF-B186, my work provides potential targets for therapies that stimulate blood vessel growth in the heart more safely and precisely than previous angiogenic treatments.
The modified VEGF-B186R127S protein is particularly promising because it promotes cardiac angiogenesis without the arrhythmias linked to the natural form of VEGF-B186. This could improve future therapeutic angiogenesis strategies aimed at restoring blood flow to oxygen-deprived heart tissue.
In addition, the discovery that VEGF-B can directly regulate genes inside the nucleus opens entirely new research directions in cardiovascular biology and may influence the future design of targeted molecular therapies.
What are the key research methods and materials used in your doctoral research?
My doctoral research combined molecular biology, cell culture, genomics, imaging, and animal models to investigate VEGF-B signaling in the heart.
Key methods included adenoviral gene transfer to deliver VEGF-B186 and VEGF-B186R127S into mouse hearts, endothelial cell culture experiments, immunocytochemistry, immunofluorescence, and subcellular fractionation to track VEGF-B localisation inside cells.
To identify novel VEGF-B receptors, I used crosslinking-based protein interaction assays and co-immunoprecipitation. I also performed ChIP-seq to identify genomic binding sites of VEGF-B and analysed RNA sequencing data to study downstream gene regulation.
The work involved both wild-type and genetically modified mice, as well as healthy and ischemic pig heart samples, linking molecular discoveries with translational cardiovascular research.
Is there something else about your doctoral dissertation you would like to share?
One of the most exciting aspects of this work is that it challenges the traditional view of how VEGF proteins function. VEGF family members have long been considered extracellular signaling molecules that act only through surface receptors. My findings suggest that VEGF-B186 can also function inside the cell nucleus as a regulator of gene activity.
This work also highlights the importance of studying full-length protein forms rather than only processed fragments, as the biological effects of VEGF-B186 changed dramatically after proteolytic cleavage. The discovery of integrins as alternative VEGF-B receptors further expands our understanding of angiogenic signaling in the heart.
Beyond cardiovascular research, these findings may influence broader fields such as cell signaling, stress biology, and regenerative medicine by introducing a previously unrecognised mode of growth factor action.
The doctoral dissertation of Rahul Mallick, MBBS, MSc, entitled Non-canonical signaling mechanisms of full-length VEGF-B186 in cardiac angiogenesis will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Matthew Griffin of the University of Galway, and the Custos will be Professor Seppo Ylä-Herttuala of the University of Eastern Finland. The public examination will be held in English.
Doctoral dissertation (link available later)
For further information, please contact:
Rahul Mallick, MBBS, MSc, [email protected], https://uefconnect.uef.fi/en/rahul.mallick/
