Lena Claesson-Welsh's research projects in vascular biology
Endothelial mechanosensing and Cardiovascular Diseases
Cardiovascular disease (CVD) is a common term for diseases implicating heart and blood vessels interactions. Coronary heart disease, stroke and aortic diseases are some of the CVDs that currently are major causes of death worldwide. Several studies have shown that endothelial cells (ECs) play a role in CVDs; however, the specific mechanisms regulating ECs and role in the development of the specific diseases have not yet been addressed. Our group focuses in understanding how mechanical forces affect the endothelium, and through the cell cytoskeleton alter EC gene regulation with profound effects on cellular behavior.
Of particular interest is the cytosolic protein Palmdelphin (Palmd), which belongs to the paralemmin family. In patients with Calcific Aortic Valve Stenosis, SNP variants present in the Palmd locus cause decreased Palmd expression levels which correlates with severity of the disease. As other paralemmin family members, Palmd has been implicated in cell shape regulation. This project aims to show whether Palmdelphin plays a role in endothelial cell shape control and mechanosensing.
Src family kinases in vascular biology
The Src family kinases (SFK) are highly related non-receptor tyrosine kinases which play important roles in normal tissue development as well as in tumorigenesis. We are interested in the roles of different SFKs in vascular developmental processes such as endothelial cell migration, proliferation, sprouting and regression.
Another part of our work focus on vascular physiology, especially how vascular permeability is regulated by the SFKs. Several mouse genetic models have been generated for the study. We use state-of-the-art imaging techniques to study cellular behaviours both in vivo and in vitro, accompanied by proteomics (SFK substrates and interaction partners) as well as transcriptomic analyses (RNA sequencing to understand SFK gene regulation), to discover novel molecular mechanisms.
Endothelial cell signaling in tumor angiogenesis, metastatic spread and its clinical significance
Tumor vessels formed by enhanced VEGFR2-signaling are abnormal and leaky, which promotes spread of cancer cells and prevents drug delivery. Targeting VEGFR2-signaling to normalize vessels is a strategy for treatment of cancer patients. However, complete blockage has only been beneficial in certain tumor types. We therefore aim to investigate the biological responses that VEGFR2 controls, and their molecular regulation.
We focus on the tyrosine phosphorylation site pY1173 in VEGFR2, and in a parallel project, the effect of the interaction between VEGFR2 and the VEGF co-receptor neuropilin1 (NRP1). By targeting specific vessel functions controlled by NRP1 or individual tyrosine phosphorylation sites, we aim to specifically suppress formation of abnormal vessels and still ensure efficient blood flow to tumors. We also aim to identify novel biomarkers to identify cancer patients who will benefit from anti-angiogenic therapy.
This far, we have shown that perivascular NRP1 is beneficial for cancer patient-survival by restricting angiogenesis (see Morin et al., 2018, 2020). Furthermore, pY1173 is essential in regulation of vascular leakage in response to VEGFA. Continued work will explore the underlying mechanism and the impact of pY1173-signaling on tumor progression and metastasis.
Endothelial cell heterogeneity and its impact on vascular permeability
In my research I am interested in better understanding endothelial cell heterogeneity and its impact on vascular permeability. Using intravital imaging (see Honkura et al., Nat Commun 2018 16;9(1):2746 for details), I directly visualise vascular leakage in response to various factors, which not only allows accurate quantitative measurements but also a qualitative assessment of the geographical locations of vascular leakage.
From these studies we have learnt that distinct sites within blood vessels and between distinct endothelial cells exhibit a higher sensitivity to stimulation and are thus more likely to leak. The molecular identity of such sites that explains these characteristics is however unclear.
Through complementary and correlative studies, I am now working to discover what distinguishes these pre-determined sites of leakage from other, less sensitive sites, with the aim of better understanding endothelial cell heterogeneity and its impact on pathological vascular processes.
Does eNOS modulate vascular permeability and angiogenesis induced by VEGF receptor-2?
It has long been known that VEGF and the corresponding receptor (VEGFR2) play an essential role in the dismantling of endothelial cell-cell (adherens) junctions, resulting in i ncreased vascular permeability and leakage of blood constituents into the surrounding tissue. This occurs by dissociation of bonds formed between endothelial cells by the adhesion protein VE-cadherin. It is still unknown how several complex and intertwined pathways that stem from the activation of VEGFR2, interact and converge to orchestrate the opening and closure of endothelial cell adhesion junctions to create a selectively and transiently permeable membrane that lines the walls of blood vessels.
We hypothesise that endothelial nitric oxide synthase (eNOS) plays a role in this signalling cascade. Historically, eNOS and its product nitric oxide (NO), have been thought to mainly contribute the dilation of blood vessels via the action of NO on surrounding smooth muscle cells.
Our research aims to explore how eNOS/NO affects VE-cadherin bonds and thereby vessel permeability, and how this effect may involve signal transducers such as Src family kinases that modulate VE-cadherin activity and stability.