An Emerging Role for Angiogenesis in Tendinopathy
Abstract
Abstract
Chronic, painful tendinopathies that result from overuse display an underlying pathology known as tendinosis. This article summarises recent findings that support a role for angiogenesis in tendinosis. Immunohistochemical and in situ hybridisation studies suggest that there may be previously unappreciated regulatory interactions between nerves, vessels, mast cells and tenocytes. These interactions could influence different aspects of the pathology, including pain, blood flow and the proliferation of nerves and vessels in tendinopathic tendons. Indeed, angiogenic peptides (e.g. vascular endothelial growth factor), neuropeptides (e.g. substance P) and enzymes (e.g. mast cell tryptase) are locally expressed in painful tendons to an increased degree compared with normal tendons. An emerging treatment strategy focuses on nerve and vessel ablation. Interestingly, following this therapy, tendon structure has been observed to normalise in some cases. Thus, angiogenic peptides and neuropeptides appear to play an important role in the persistence of tendinosis pathology; interfering with nerves and vessels may be able to directly address this aspect of the pathology.
Keywords
Tendon, tendinopathy, tendinosis, angiogenesis
Disclosure: The authors have no conflicts of interest to declare.
Received: 21 August 2008 Accepted: 1 October 2008
Correspondence: Alex Scott, Biomedical Research Centre, 2222 Health Sciences Mall, Vancouver, BC V6T 173, Canada. E: Ascott@interchange.ubc.ca
Viennese philosopher Karl Popper, the father of scientific reasoning, wrote that “science must begin with the criticism of myth”. It is with this in mind that Khan et al. have re-examined the histology underlying chronic tendinopathies, concluding that the pathology formerly known as ‘tendinitis’ is better decribed as ‘tendinosis’ – acondition characterised by the proliferation of vascular tissue and the disruption of normal tendon architecture.1 If tendinitis is a myth to be abandoned, after Khan et al., tendinosis provides the basis for new theories regarding the cause of chronic tendon pain.
So, what is tendinosis? It is a degenerative state of tendon tissue, characterised primarily by an increased presence of fibro-vascular (reparative) tissue.2 This tissue is hypercellular, rich in glycosaminglycan and characterised by thin, disorganised (mostly type III) collagen.3,4 Commonly, there is phenotypic change within the tendon as well: usually chondroid change and, occasionally, bony change.5 Inflammatory cells are scarce or absent. Tenocytes display evidence of ongoing proliferation as well as cell death, indicating an abnormal increase in the rate of cellular turnover.6,7 In summary, tendinosis appears to be the evidence of a ‘failed healing response’ – the body’s unsuccessful attempt to repair the tendon following an accumulation of overuse injuries.
Tendinosis should not be confused with age-related tendon degeneration.8,9 Age-related degeneration is primarily characterised by a loss of tenocyte numbers, not by the expansion of vascularity. Age-related degeneration is typically asymptomatic and occurs in the absence of extensive neovascularisiation. It is not yet known which features of tendinosis lead to chronic tendon pain. However, the increased presence of vessels – and their accompanying nerves – is a leading candidate.10
A promising new therapy that specifically targets nerves and vessels as they enter the tendon is the use of sclerosing injections. This approach has been successfully used to treat both Achilles and patellar tendinopathies. 11,12 The same rationale underlies the use of minimally invasive surgical procedures that disrupt the neurovascular structures as they enter the tendon. 13 In both approaches, treatments are performed with the aid of colour Doppler ultrasound to visualise the vessels before and immediately after treatment. The disruption of flow within the tendon is associated with successful treatment. 11,12
These findings raise many interesting questions and may allow us to understand how chronic tendon pain develops in the first place. Do the increased blood vessels seen on colour Doppler ultrasound correspond to the number of vessels in the tissue? If so, could this process also lead to an increased number of nerves in the tendon and, therefore, a state of pain and irritability?
Collaborative research recently undertaken in Sweden, Canada and Norway has examined the vascular and neural tissue that is excessively present in the patellar and Achilles tendons of patients with long-standing tendinopathy. 6,14–24 In addition to confirming previous reports regarding the prevalence of tendinosis and the absence of tendinitis, the studies generated some new insights about the nerves and vessels in the painful area that suggest there may be an association between pain and neurovascular changes resulting from overuse.
First, the vessels that were present in tendinopathic tissue were accompanied by both sensory and autonomic nerve fibres. Nerves stained positively for substance P and calcitonin-gene-related peptide (CGRP) (sensory nerves), acetylcholine esterase (parasympathetic) and tyrosine hydroxylase (sympathetic). 14–18 This provides the anatomical basis for understanding that pain may originate from the injured tissue, vessels may be used as a visual clue to the location of the nerves and interfering with the nerves/vessels may influence both the transmission of pain and the local regulation of blood flow.
