Angiogenesis, stem cells, eNOS and inflammation – the many faces of vascular biology

Vascular biology has been a very exciting scientific field over the past few decades, bringing significant input into the mechanisms of vascular diseases, and, more recently, expanding it’s insights much further into cancer biology, metabolic disorders as well as immunology. Moreover, growing understanding of both pathophysiology and molecular biology of the vasculature has reached the point at which we can start introducing specific therapies affecting angiogenesis as well as vascular nitric oxide homeostasis to treat wide variety of conditions. Papers in the present theme issue of Thrombosis and Haemostasis reflect such the wide range of vascular biology approaches starting from vascular inflammation (1, 2), through therapeutic angiogenesis (3), to mechanisms of endothelial inflammation and angiogenesis (4–6), all of which can subsequently affect thrombosis (7). Recent understanding of nitric oxide synthase (NOS) biology has directed our attention to tetrahydrobiopterin (BH4), the role of which in regulation of eNOS and iNOS function has been addressed in the review by McNeill and Channon (4). Besides addressing the significance of BH4 in the activity of endothelial NOS, which uncoupling has been linked to the enhanced reactive oxygen species (ROS) production in the vascular system, the authors have elaborated also the role of BH4 in the inducible NOS function. This appears to point to the role of BH4 in the regulation of inflammation. The increasing evidence that BH4 is involved in regulation of the function of multiple immune cell types opens up an exciting new field, particularly as this coincides with the recognition that conditions such as hypertension may have a strong immune component (8). This opens new possibilities for the modulation of multiple pathophysiological processes, which involve inflammatory responses such as cancer, chronic inflammatory and autoimmune disorders and others. Indeed neopterin, a metabolite of pterin pathway, has been considered a marker for inflammation for a very long time, but now the role of pterins may turn out to be much more important than just unspecific markers of inflammation. Moreover it may link genetic variability of GTP-cyclohydrolase-1 (GCH1) gene to susceptibility of multiple disorders (9). Interestingly, a recent study (10) showed that treatment with BH4 before ischaemia/ reperfusion (I/R) in the heart of diabetic rats reduced superoxide generation by iNOS and increased NO bioavailability, leading to the reduction in infarct size and improvement of left ventricular function after I/R. Interestingly, that work showed that cardioprotective effects of BH4 was abolished by DTT, a thiol-reducing agent but not by inhibition of soluble guanylyl cyclase, indicating the importance of S-nitrosylation rather than cGMP production in the signalling in diabetic heart (10) . The enzymes generating NO have numerous functions and one of them is involvement in the blood vessel formation. Some previous studies (11, 12), supported by other observations (e.g. [13, 14]) demonstrated the significance of NO for iNOSdependent generation of VEGF by different cell types, including vascular smooth muscle cells. In those studies (11, 12) both inhibition of NOS activity by L-NAME, as well as attenuation of GTP-cyclohydrolase activity with diaminohydroxypyrimidine (DAHP) led to the reduction of VEGF synthesis which was restored by supplementation with L-arginine or BH4. However, a current study published in this Theme Issue of Thrombosis and Haemostasis (6) indicates more complex interactions. The study by Petry et al. suggests that in endothelial cells inhibition of NO synthase increases capillary formation via Rac1-dependent induction of HIF-1 and PAI-1. This study claims that proangiogenic effect of thrombin is dependent on ROS formation which enhanced HIF-1, PAI-1 and capillary formation, and that concomitant NO release exerted anti-angiogenic effect by reducing ROS bioavailability (6). Although the final effect of ROS/NO on angiogensis is undoubtedly the consequence of interaction of numerous pathEV BM 2 01 1 (P ar t 2)