Objectives: 

Activin receptor-like kinase-1 (ALK-1) is a type I receptor for TGF-beta with serine/threonine kinase activity mainly expressed in vascular endothelial cells. A mutation in the gen that codifies for ALK-1 is the responsible for a disease named Hereditary Hemorrhagic Telangiectasia type 2 (HHT-2). Another form of the disease, HHT-1 is caused by mutations in endoglin, another co-receptor of TGF-beta. We have demonstrated that endoglin plays a major role in vascular contractility regulation by regulating eNOS expression (Am J Physiol 299:H959-H974; 2010). As the alterations in the vascular reactivity seem to play a role in the HHT-1 and pulmonary hypertension, the aim of our study was to test the role of ALK-1 in the regulation of the vascular function.

Materials: 

For this purpose we have used mice with only one functional copy of the gen (Alk-1+/­), a genotype similar to the disease. Arterial pressure (AP) was measured using a telemetry system to avoid the alterations induced by anesthesia and movement restriction. We have also performed western blot, PCR and other molecular biology techniques.

Results: 

Alk-1+/­ mice had a higher arterial pressure (AP) than control mice (Alk-1+/+). Acetyl-choline or nitroprusside treatment induced a similar decrease in AP in both mice strains, whereas L-NAME treatment induced the same AP increase in both groups, thus suggesting that ALK-1 effect on the AP is nitric oxide-independent. Administration of losartan or captopril reduced AP more in Alk-1+/­ than in Alk-1+/+ mice suggesting an alteration in the renin-angiotensin-system. Plasma angiotensin II concentration was lower in Alk-1+/­ than in Alk-1+/+ mice. Administration of Tempol, a superoxide-dismutase mimetic decreased AP significantly more in Alk-1+/­ than in Alk-1+/+ mice.

Conclusions: 

In conclusion, the increase in arterial pressure observed in the Alk-1+/­ mice could be based on alterations in the renin-angiotensin system and in oxidative stress.