| Regulation of cardiac responses to increased load: Role of endothelin-1, angiotensin II and collagen XV | ||
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Despite the wide occurrence of type XV collagen in basement membranes throughout the body, mice lacking it are viable and fertile (V). However, the Col15a1-/- mice showed increased sensitivity to exercise-induced muscle damage. Despite the antiangiogenic role of type XV collagen-derived endostatin (Ramchandran et al. 1999), no abnormalities in the number of vessels could be observed. Instead, type XV collagen appeared to play a role in the integrity of the microvessels, since its deficiency was found to lead to an apparent collapse of the capillary wall in the heart and skeletal muscle, resulting in various degrees of narrowing or obstruction of the capillary lumen and EC degeneration and swelling. Morphologically similar degenerative changes in capillary ECs have been observed in experimental models for the ischemic (Armiger & Gavin 1975) and reperfused (Ward & McCarthy 1995) myocardium and in patients with small vessel disease (Mosseri et al. 1991), microvascular angina, hypertrophic cardiomyopathy or dilated cardiomyopathy (Suzuki et al. 1995). Those previous observations suggest that the EC degeneration and swelling in Col15a1-/- mice may be caused by impaired microvasculature perfusion and ischemic damage to the endothelium. Immunostaining studies (Muona et al. 2002) have indicated that while type XV collagen is associated with most capillaries in adult mice, including those in the heart and the skeletal muscle, there are some tissues, including the mature lung and brain, in which it is not detected around the capillaries. The fact that the lung and brain capillaries of the null mice were normal further confirms that the defects seen in the heart and skeletal muscle capillaries are due to a lack of type XV collagen.
The exercise protocol was optimized for studying skeletal muscle injury, and the timing for analysis could cause limitations for the markers used to study cardiac injury, since the maximal responses in the expression of MMP-2 (Cleutjens et al. 1995) and ANP (Hama et al. 1995) are reached later than 48 hours after acute cardiac injury and the apoptotic effects earlier (Kajstura et al. 1996). Interestingly, the basal MMP-2 activities were found to be significantly lower in the Col15a1-/- mice than in the wild-type ones. Since MMP-2 is expressed by ECs (Lewalle et al. 1995), this could suggest loss of ECs and coincide with the identified EC degeneration.
As the organization and function of the heart as a continually contracting muscle differs from that of skeletal muscle, acute exercise is not likely to lead to similar injuries to those affecting the latter. The abnormalities in the heart microvasculature observed at the morphological level will most probably cause marked ischemic-like damage only upon loading. This has been observed with young mice lacking δ-sarcoglycan, where the primary causes of the heart phenotype is thought to be a perturbation in vascular function. In both δ-sarcoglycan (Coral-Vazquez et al. 1999) and type XV collagen-deficient mice acute exercise caused cardiac injury before the development of apparent cardiomyopathy. Furthermore, the preservation of the histological integrity of the heart tissue in the Col15a1-/- mice supports the hypothesis that a certain degree of vascular dysfunction may be required to reach the ischemic threshold necessary to induce myocardial necrosis, as proposed by Corel-Vazquez et al. (1999).
The isolated perfused hearts of Col15a1-/- mice showed decreased responses to a β -AR agonist. Reduced responsiveness to β -AR stimulation is associated with chronic heart diseases (Bristow et al. 1982) and with ageing (Lakatta 1999). Hearts suffering from chronic diseases have multiple changes in β -AR-mediated events, including the expression and function of β -adrenergic receptors, G-proteins, AC and G-protein receptor kinases (Post et al. 1999). Down-regulation of β 1-AR receptors has been suggested to occur at an early stage in the development of heart failure (Kiuchi et al. 1993). In humans, reduced β 1-AR mRNA levels (Engelhardt et al. 1996) and receptor density (Fowler et al. 1986) are also detected in a mild form of cardiac dysfunction, indicating that down-regulation of β -AR receptors is not restricted to severe heart disease. Moreover, histological analysis of cardiac tissue from volume-overloaded pigs indicates that decreased responsiveness to β -AR stimulation can occur without degenerative changes such as inflammation or fibrosis (Hammond et al. 1992).
Microvasculature defects are involved in the initiation and progression of heart failure and cardiomyopathy in some modes of human heart disease (Gavin et al. 1998). Microcirculation abnormalities have been demonstrated earlier in Syrian hamsters suffering from cardiomyopathy (Factor et al. 1982), together with a decreased response to isoproterenol, indicating changes in β -AR signaling pathways (Feldman et al. 1990). The desensitization of β -AR signaling observed in Col15a1-/- mice is a hallmark of heart failure, and the microcirculation defect may be contributing to cardiac dysfunction.
In view of its collagenous primary structure, its location in the extracellular space and the consequences of the loss of its function, it could be assumed that type XV collagen functions as a structural component which is needed to stabilize cells with the surrounding connective tissue. Data also suggest that a lack of type XV collagen will cause damage to the heart in connection of induced cardiovascular stress. It is possible that this deficiency may cause mild cardiac dysfunction, detectable first as a diminished inotropic response to isoproterenol. Interestingly, these changes mimic early or mild heart disease with respect to features such as decreased inotropy and impaired response to exercise. The microvascular defects are more pronounced in the heart than in skeletal muscle and are accompanied by ischemic changes in the ECs and adjoining cardiomyocytes, and the heart phenotype may be due to impaired microcirculation.