Systemic Production of Vascular Endothelial Growth Factor and fms -Like Tyrosine Kinase-1 Receptor in Acute Kawasaki Disease

Abstract

Background — Increased vascular permeability is an important event during the initial process of Kawasaki disease (KD). One potential responsible candidate for the induction of vascular hyperpermeability is vascular endothelial growth factor (VEGF). Methods and Results — We investigated the expression of VEGF and its receptors (flt-1, KDR) in acute KD tissues at 7 days to 5 weeks of illness. Neuropilin-1, which enhances the binding of VEGF 165 to KDR, was also studied. Abundant expression of VEGF and flt-1 was documented immunohistochemically in many organs from acute KD, including heart and lung. VEGF and flt-1 were colocalized in all vessels that showed edema. These molecules resided in endothelium and vascular media and also in migrating smooth muscle cells in neointima and infiltrating macrophages. Compared with controls, coronary vessels of acute KD had upregulation of VEGF and flt-1 but not KDR or neuropilin-1. KDR was expressed by vessels at 7 days of illness but not later in the illness. Plasma proteins were more extensively bound to the extracellular matrix in coronary vessels in acute KD than controls. Furthermore, elevation of serum VEGF levels was correlated with low serum albumin in acute KD (n=220, r =−0.53, P <0.001). Conclusions — These findings suggest that VEGF and flt-1 are upregulated in blood vessels in many organs of acute KD. Expression of KDR was limited to the early stage of acute KD. The roles of VEGF in acute KD may involve promotion of vascular permeability and macrophage activation. Low serum albumin may indicate overproduction of VEGF in acute KD.

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association

“…46 Vascular endothelial growth factor (VEGF), monocyte chemotactic and activating factor (MCAF or MCP-1), tumor necrosis actor-␣ (TNF-␣), and various interleukins also appear to play important roles in the vasculitic process. [47][48][49][50][51][52][53][54] …”

Imbalance in the production between vascular endothelial growth factor and endostatin in Kawasaki disease

“…In fact, pathological studies have revealed that CAL in KD are characterized by subendothelial oedema, vascular EC damage and the infiltration of inflammatory cells [21,22]. On the other hand, an active remodeling process has been reported to occur in the CAL of acute KD [14,15] which thereafter continues several years after the onset of KD [16]. VEGF can recruit endothelial progenitor cells from the bone marrow into the peripheral circulation [23].…”

“…Yasukawa et al . [14] reported that CAL in acute KD had abundant expression of VEGF and its receptors. Matrix matalloproteinases (MMP)-2 and -9 were expressed at the CAL in KD, thus suggesting that angiogenesis occurs in the remodeling process of the arterial walls in acute KD vasculitis [15].…”

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease

“…46 Vascular endothelial growth factor (VEGF), monocyte chemotactic and activating factor (MCAF or MCP-1), tumor necrosis factor-␣ (TNF-␣), and various interleukins also appear to play important roles in the vasculitic process. [47][48][49][50][51][52][53][54] …”