ADMA, angiogenesis and clinical complications in sickle cell disease

PhD ceremony: Ms. P.P. Landburg, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: ADMA, angiogenesis and clinical complications in sickle cell disease

Promotor(s): prof. A.J. Duits

Faculty: Medical Sciences

Sickle cell disease (SCD) is worldwide one of the most common inheritable diseases. Originally the disease was seen in Africa, Saudi-Arabia, India and Mediterranean countries. Due to immigration from Surinam, the Caribbean and Africa the prevalence of SCD is increasing in the Netherlands. Sickle hemoglobin is caused by a single point mutation in the β-globin gene which forms polymers when in deoxygenated state. SCD is characterized by chronic hemolysis, increased susceptibility for infections (due to functional asplenia) and complications such as vaso-occlusive pain crises, pulmonary hypertension and stroke. Organ damage in SCD has a multifactorial origin, in which hemolysis, hypoxia and angiogenesis play an important role. Angiogenesis and the process of vacular remodelling contribute to the morbidity in SCD. Hemolysis and hypoxia result in a characteristic decreased nitric oxide (NO) bioavailability.

In this thesis the roles of angiogenesis and specific factors influencing the bioavailability of NO in SCD and related complications are described. We did not find a relation between the altered angiogenic factor concentrations and the formation of SCD-related complications which does not exclude a role for angiogenic factors in the development of SCD-related complications. Our findings merely point out the complexity of the angiogenic response and pathophysiology of SCD. NO plays a central role in the vascular homeostasis and we showed that asymmetric dimethylarginine (ADMA) contributes to a reduction of NO bioavailability during the clinical asymptomatic state en possibly plays an important role in the development of SCD-related pulmonary hypertension.