Angiogenesis in Inflammation: Mechanisms and Clinical Correlates

Abstract

Normal wound healing includes a number of overlapping phases. After injury, there is an early inflammatory step characterised by haemorrhage and clotting. At this time, the wound has a provisional serum-derived extracellular matrix, which serves to seal the wound temporarily and allows the invasion of cells that carry out the repair process. In the next phase, consisting of granulation tissue development, fibroblasts invade the wound and commence replacing the provisional matrix with a more mature wound matrix. The fibroblasts present during the early granulation tissue phase resemble immature fibroblasts with a highly synthetic appearance. However, as the granulation tissue phase proceeds, fibroblasts start showing a new phenotype with prominent contractile structures represented by microfilament bundles or stress fibres; these structures express contractile proteins typical of smooth muscle cells, particularly of vascular smooth muscle cells, such as α-smooth muscle actin [1]. Recently, it has been shown that α-smooth muscle actin is largely responsible for force production by the myofibroblast both in vitro and in vivo. Myofibroblast differentiation is a complex process, regulated, by at least one cytokine [transforming growth factor (TGF)-β1] [2], an extracellular matrix component (fibronectin ED-A) [3] as well as the presence of mechanical tension [4] (for review, see [5]). Lastly, in the resolution phase of healing, there is considerable loss of cellularity essentially through apoptosis of several cell types including myofibroblasts [6]. Normal wound healing includes a number of overlapping phases. After injury, there is an early inflammatory step characterised by haemorrhage and clotting. At this time, the wound has a provisional serum-derived extracellular matrix, which serves to seal the wound temporarily and allows the invasion of cells that carry out the repair process. In the next phase, consisting of granulation tissue development, fibroblasts invade the wound and commence replacing the provisional matrix with a more mature wound matrix. The fibroblasts present during the early granulation tissue phase resemble immature fibroblasts with a highly synthetic appearance. However, as the granulation tissue phase proceeds, fibroblasts start showing a new phenotype with prominent contractile structures represented by microfilament bundles or stress fibres; these structures express contractile proteins typical of smooth muscle cells, particularly of vascular smooth muscle cells, such as α-smooth muscle actin [1]. Recently, it has been shown that α-smooth muscle actin is largely responsible for force production by the myofibroblast both in vitro and in vivo. Myofibroblast differentiation is a complex process, regulated, by at least one cytokine [transforming growth factor (TGF)-β1] [2], an extracellular matrix component (fibronectin ED-A) [3] as well as the presence of mechanical tension [4] (for review, see [5]). Lastly, in the resolution phase of healing, there is considerable loss of cellularity essentially through apoptosis of several cell types including myofibroblasts [6].