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Doctoral defence of Galina Wirth, MSc, 1 March 2024: Microvascular dynamics are a promising therapeutic target in lower extremity artery disease

The doctoral dissertation in the field of Vascular Biology will be examined at the Faculty of Health Sciences at Kuopio campus. The public examination will be streamed online.

What is the topic of your doctoral research? Why is it important to study the topic?

Lower extremity artery disease (LEAD) is a significant health problem, causing death and disability in the elderly population. In LEAD atherosclerotic arterial blockages limit blood flow to the legs. The disease progressively deteriorates muscle function, causes tissue damage and over time can result even in the need of limb amputation. Clinical management of LEAD is focused on the prevention and treatment of atherosclerotic blockages. Unfortunately, these strategies yield only suboptimal results and novel treatment options would be highly required. 

The muscle microvasculature is a key regulator of skeletal muscle function. However, the muscle microvasculature is not routinely assessed in LEAD patients. Better understanding of how the microvasculature could support muscle recovery in LEAD could help improve patient outcomes. This doctoral research investigated how the microvasculature affects muscle damage and repair after experimental arterial blockage. 

What are the key findings or observations of your doctoral research?

This doctoral research uncovered the importance of the microvasculature in differentiating between muscle damage and repair after arterial blockage. These results depict a much greater role for the microvasculature in muscle recovery than previously acknowledged. The microvasculature needs to dynamically adjust to the needs of the tissue in order to efficiently support tissue recovery. The dynamic changes of the muscle microvasculature were found to be associated, beyond muscle survival, with changes e.g., in arterial driving pressure and hemoglobin oxygenation. The results describe a chain of microvascular events required for successful muscle recovery. The research also describes how hyperlipidemia can impair microvascular reactivity and result in chronic muscle damage similar as in LEAD.

How can the results of your doctoral research be utilised in practice?

This doctoral research has explained the biological relevance of the dynamic changes of the muscle microvasculature after arterial blockage. This knowledge greatly advances our understanding of basic microvascular behavior under disease conditions. The work identifies microvascular dynamics as a promising therapeutic target to improve post-ischemic skeletal muscle recovery. The results may also help to explain the lack of efficacy of previous pro-angiogenic treatment strategies tested in clinical trials. Based on these results, neither the increase in capillary size nor the increase in capillary density alone, are sufficient to promote skeletal muscle repair. The timing and dynamics of capillary changes are of the essence.

What are the key research methods and materials used in your doctoral research?

This doctoral research is a translational study combining data from animal models and LEAD patients. In the animal models, several high-resolution imaging techniques were combined with histological assessment of muscle samples to investigate microvascular structure and function together with myofiber morphology. An animal model of acute arterial blockage with or without hyperlipidemia in aged mice was used. Furthermore, a gene therapy approach was employed to modify the microvascular behavior. Contrast-enhanced ultrasound was used to follow microvascular blood flow. Photoacoustic imaging was utilized to follow microvascular hemoglobin oxygenation changes. Doppler ultrasound imaging was used to follow macrovascular blood flow. Magnetic resonance imaging was employed to follow tissue edema and myofiber regeneration. Additionally, a unique collection of skeletal muscle samples from LEAD patients was gathered at Kuopio University Hospital and analyzed to compare myofiber pathology resemblance between LEAD and the used animal models.

The doctoral dissertation of Galina Wirth, MSc, entitled Microvasculature in post-ischemic muscle damage and regeneration - Lower limb ischemia studies will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Associate Professor Riikka Kivelä of the University of Jyväskylä, and the Custos will be Professor Seppo Ylä-Herttuala of the University of Eastern Finland.

Doctoral defence 


Dissertation (link available later)

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