The heart regenerates poorly in mammals; functional tissue is replaced by scar tissue following injury, such as a the damaged caused in a heart attack. Researchers have recently found that type V collagen is an important determinant of the extent of this scarring, which varies considerably from individual to individual. Greater scarring leads to worse heart muscle function and a poor prognosis for the patient.

Genetic engineering of animals to remove the capacity to generate this type V collagen increases scar size following the induction of a heart attack. Researchers here show that this results because differences in the mechanical properties of scar tissue lacking type V collagen cause greater efforts on the part of cells to try to reinforce and expand the scar. This discovery may or may not point the way towards strategies to minimize scar formation in heart tissue; that remains to be seen.

Following acute myocardial infarction (MI), dead cardiac muscle is replaced by scar tissue. Clinical studies demonstrate that scar size in patients with prior MI is an independent predictor of mortality and outcomes, even when normalized with respect to cardiac function. Despite the immense pathophysiologic importance of scar burden, little is known about factors that regulate scar size after ischemic cardiac injury.

To identify factors determining scar size after MI, we subjected animals to ischemic cardiac injury and performed transcriptional profiling of heart scars isolated from 3 days to 6 weeks post injury. We observed that scars rapidly attained transcriptional maturity, and there were minimal transcriptional changes in the maturing scar tissue beyond 2 weeks of injury. We thus hypothesized that genes that regulate scar size are likely to be differentially expressed early after ischemic injury. Collagens were one of the most highly differentially upregulated genes in the injured heart early after ischemic cardiac injury.

In this report, we demonstrate that collagen V (Col V), a fibrillar collagen that is minimally expressed in the uninjured heart and a minor component of scar tissue, limits scar size after ischemic cardiac injury. Animals lacking Col V in scar tissue exhibit a significant and paradoxical increase in scar size after ischemic injury. In the absence of Col V, scars exhibit altered mechanical properties that drive integrin-dependent mechanosensitive feedback on fibroblasts, augmenting fibroblast activation, extracellular matrix (ECM) secretion, and increase in scar size.

A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.