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Research carried out by the recipents of the Young Investigator Grants (YIG)

One key mission of the Cardiovascular Program at KI is to support young and promising researchers in the cardiovascular field, preferably recruited from international top universities other than KI. To achieve this goal, CVP has announced Young Investigator Grants (YIG). All candidates are evaluated by three external referees.

 

Lars Jakobsson

All tissues of the human body require nutrients and oxygen and the delivery of immune cells for their survival and expansion, hence vessels are present everywhere. This also brings that abnormal blood vessel function is a major component in the progression of, or even development of, several diseases such as cancer, diabetic retinopathy, trauma, stroke complications, hereditary haemorrhagic telangiectasia (HHT) and ischemic heart disease. My lab is studying how the vasculature can reorganise and expand into the intricate network of arteries, veins and capillaries, to functionally meet the precise demand from tissue. In this process the interplay between the major units of the vasculature; the endothelial cells (ECs), the supportive mural cells, and their shared basement membrane (BM) is crucial.  The properties of these different components also dictate the functional aspects of the vessels such as permeability and constriction/dilation.

In our studies we mimic pathological situations by genetically disrupting components of the vascular wall. We target either the laminins of the vascular BM, the interaction between pericytes and ECs or the Transforming growth factor beta coreceptor endoglin. A mutation in endoglin causes the human disease HHT, characterised by nosebleeds, dermal micro aneurysms and sometimes lethal arterial-venous malformations of the brain. Endoglin is expressed by ECs and is known to be upregulated in inflammation and angiogenic tissues.

In combination with deletion of the respective gene of interest we use fluorescent reporters to follow the cells during development (lineage tracing). Specific reporters with differential fluorescence in pericytes and ECs also allow for detailed imaging of the cellular interplay by high resolution time-lapse microscopy. We hope that our analysis will gather new information on how the components of the blood vessel wall affect angiogenesis, vascular stability and function. In turn an increased understanding of these cellular interactions may provide significant impact on the development and refinement of treatments of several diseases.

The vasculature of the developing retina.
Endothelial cells (blue), pericytes (red) and
astrocytes (white) interact to form the
functional vasculature.
Modelling diabetic retinopathy.
Pathological angiogenesis of the retina occurs as a consequence of hypoxia.
Dysfunctional microvascular tufts (spheres of dividing endothelial cells, green) form and are tightly associated with macrophages (red/yellow). Cell nuclei are in blue.