Clinical relevance of vascular endothelial growth factor levels in sickle cell disease

Abstract

In recent years, vascular inflammation, marked by activated monocytes and endothelium, has been proven to play a significant role in the pathogenesis of vaso-occlusive events (VOEs) in sickle cell disease (SCD). Vascular endothelial growth factor (VEGF), an endothelial cell mitogen, has been shown to contribute to the increased endothelial cell adhesivity by increasing the expression of cell adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) on the endothelium. We have investigated VEGF alterations in 37 patients with SCD during VOEs and/or steady state. VEGF levels (mean+/-SEM) were found to be significantly elevated during VOEs (703.1+/-119.0 pg/ml) when compared with those at steady state (258.0+/-57.8 pg/ml) and healthy controls (196.6+/-21.9 pg/ml) (p<0.001). However, we did not find a difference between VEGF concentrations in sickle patients at steady state and the normal subjects (p>0.05). We suggest that considering a possible stimulatory role of tissue hypoxia in VEGF production during VOEs, VEGF levels in sickle patients might be helpful in monitoring disease severity.

Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease

“…19,20,37 LDH also correlates with endothelial-derived soluble adhesion molecules, considered markers of endothelial activation that are normally repressed by NO. 2,4,5,8,[38][39][40][41][42][43][44] Most significant from a clinical perspective, steady-state LDH elevation furthermore identifies a subset of patients in our cohort with sickle cell disease at risk for pulmonary hypertension, cutaneous leg ulceration, priapism, and early death. This supports the concept, first advanced by Ballas and more recently by Alexander and colleagues, that a subgroup of patients with sickle cell disease suffers frequent leg ulcers, independent of the frequency of VOC crisis.…”

Serum levels of angiogenic factors indicate a pro‐angiogenic state in adults with sickle cell disease

“…Two other studies addressed VEGF plasma levels in SCD with discrepant results (Solovey et al, 1999;Gurkan et al, 2005). As circulating VEGF levels are largely cell-associated, the use of serum instead of plasma for VEGF determination has been advocated, as this would yield more representative and reliable results (Gunsilius & Gastl, 1999).…”

Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1α expression in normoxic sickle mice: microvascular implications

“…Activation of HIF is implicated in cellular adaptive responses to hypoxia and inflammation. HIF can trigger transcription of genes for vasoactive molecules such as vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), and endothelin (29,52,58), which are implicated in the pathophysiology of SCD (14,21,22,42,54).HIF-1 is a heterodimeric transcription factor consisting of two subunits, i.e, HIF-1␣ and HIF-1␤. HIF-1␣ is induced during hypoxic (or inflammatory) conditions, while HIF-1␤ [also known as aryl hydrocarbon nuclear translocator (ARNT)] is constitutively expressed (26,29,51).…”

“…Activation of HIF is implicated in cellular adaptive responses to hypoxia and inflammation. HIF can trigger transcription of genes for vasoactive molecules such as vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), and endothelin (29,52,58), which are implicated in the pathophysiology of SCD (14,21,22,42,54).…”