The role of vasculature and angiogenesis for the pathogenesis of degenerative tendons disease

Abstract

More than 100 years ago Wilhelm Roux (1895) introduced the term "functional adaptation to anatomy and physiology". Compared with other organ systems the functional adaptation processes are best identifiable in the locomotor system, like for example in the two types of tendons: traction and gliding tendons. Traction tendons are tendons where the direction of pull is in line with the direction of the muscle (e.g. Achilles tendon). Gliding tendons (e.g. tibialis posterior tendon) change direction by turning around a bony or fibrous hypomochlion. In this region the tendon is subjected to intermittent compressive and shear forces and the extracellular matrix consists of avascular fibrocartilage. Avascularity is considered to be a key factor for the etiology of degenerative tendon disease. The repair capability after repetitive microtrauma is strongly compromised in avascular tissue of gliding tendons. Reduced vascularity is not a specific feature of gliding tendons; several studies have shown that the number and size of blood vessels are largely shortened in the waist of the Achilles tendon. However, histological biopsies from degenerated Achilles tendons and Doppler flow examinations revealed a high blood vessel density in patients with degenerative tendon disease. Angiogenesis is mediated by angiogenic factors and recent studies have shown that the vascular endothelial growth factor (VEGF) is highly expressed in degenerative Achilles tendons, whereas VEGF expression is nearly completely downregulated in healthy tendons. Several factors are able to upregulate VEGF expression in tenocytes: hypoxia, inflammatory cytokines and mechanical load. Since VEGF has the potential to stimulate the expression of matrix metalloproteinases and inhibit the expression of tissue inhibitors of matrix metalloproteinases tissue inhibitor of metalloproteinases (TIMP) in various cell types (e.g. endothelial cells, fibroblasts, chondrocytes), this cytokine might play a significant role for the pathogenetic processes during degenerative tendon disease. An animal experiment in the rabbit has shown that local injection of VEGF reduced the material properties of the Achilles tendon. These experimental findings are in accordance with clinical results that a locally administered (in the area with neovascularization) sclerosing drug (Polidocanol) has a beneficial effect on chronic mid-portion Achilles tendinosis. In conclusion, decreased and increased vascularity might be involved in the pathogenesis of degenerative Achilles tendon disease.

The Achilles Tendinopathy: Pathogenesis Review

“…the tendon of coracobrachialis muscle). The biomechanical behavior of gliding tendons is fundamentally different from a traction tendon where only tension forces exist; in the contact area between a gliding tendon and the pulley there are strong compressive forces decreasing continuously towards the periphery, while the tensional forces are at their maximum at the outer part of the gliding area and decrease towards the contact area [24] . The overlapping of pressure and tension in the transition zone results in shear stress.…”

“…The overlapping of pressure and tension in the transition zone results in shear stress. The Achilles tendon, under mechanical aspects, is a traction tendon, but its structure doesn't correspond to a traction tendon: gastrocnemius and soleus fibres rotate as they descend to the calcaneal insertion (from anterior to medial the soleus fibres, from posterior to lateral the gastrocnemius ones): such spiralization, the so-called "twisting", confers a mechanical advantage to the tendon but produces an area of concentrated stress where the rotation becomes more marked (approximately 2-7 cm proximal to the insertion onto the calcaneus [17] ; this region is also named Achilles tendon waist [25] : like the waist of a wasp it is reduced in diameter and, as already mentioned, many studies reveal a hypovascularized area in the tendon waist [20] that should be considered an adaptation to the mechanical function and not a sign of degeneration (according to the theory of "causal histogenesis" by Pauwels [24] ). The structure, composition and organization of the matrix of tendons are critically important for their physical properties.…”

“…Malalignment is proposed to increase forefoot pronation, limit mobility of the subtalar joint, decrease/increase the range of motion of the ankle, lead to varus deformity of the forefoot and increase hind enzymes activities in tendon are consequently likely to have a role in tendinopathy; among them there are cytokines and growth factors [27] . Hypoxia condition determines tendon weakening: VEGF up-regulate MMPs production and down-regulates TIMP [24,28,[77][78][79][80] while favoring tissue invasion by new vessels: this is the core of the pathogenetic role of tendon hypervascularization. Recently was demonstrated that hypoxia increases collagen type III synthesis at the expense of type I; such phoenotypical change in the extracellular matrix is detrimental since the greater is the content in collagen type III, the lower is the resistance of tendon to tensile forces [81] ; when neovascularization occurs, producing further weakening of the tendon, the risk of rupture is amplified.…”

“…From a functional perspective, it is possible to distinguish between two types of tendons, depending on the main course of a muscle and its tendon [24] : traction and gliding tendons. Gliding tendons (e.g.…”

Short-Term Efficacy of Etamsylate Injection in Chronic Patellar Tendinopathy

“…In approximately 10% of conservatively treated patients, conservative treatment fails and surgery is required [3]. Since tendinopathy appears to be a highly active process of ongoing neovascularization, anti-angiogenic therapies could be a new approach for treating tendinopathies [4]. It has been reported that nerves appear to travel in close association to tendon neovessels [5].…”