Abstract 1453: Evidence for Increased Neointima Formation in Podocan Knockout Mice compared to C57/BL6 Wild Type Mice After Arterial Denudating Injury
Background: Acute arterial lesions form when endothelial and smooth muscle cells proliferate and migrate to sites of injury. This activity is regulated in part by small leucin-rich repeat proteins (SLRP) that are capable of binding extracellular matrix and growth factors to regulate cellular response. Podocan is a novel member of the SLRP family and is expressed in vascular smooth muscle cells. To explore its biological activity, we created knockout mice deficient in podocan and explored the response to vascular injury.
Methods and Results: We examined the effects of podocan genotype on femoral arterial injury in C57/BL6 wild type (WT) mice (n=10) and syngeneic C57/BL6 mice either hetero- (n=15) (HET) or homozygous (n=15) (KO) for the podocan knockout genotype. KO mice showed significantly increased neointima formation at 4 weeks after arterial injury compared to WT mice (11.6±1.8 vs. 4.4±1.3 x10–3mm2, P<0.01). Media area and overall arterial size were not different between the two groups (14.5±0.8 vs. 14.8±2.0 x10 –3mm2, P=NS, and 50.5± 5.0 vs. 53.6±14.0 x10 –3mm2, P=NS, respectively). Consistently, neointima to media ratio was strongly increased in KO mice (0.82±0.12 vs. 0.33±0.10, P<0.01). Neointima cell density did not show a significant difference between KO and WT mice reflecting increased synthesis of extracellular matrix material by proliferating cells. When comparing HET mice to WT mice, a similar trend of data was observed, however, it did not reach statistical significance.
Conclusions: This study represents the first in vivo evidence that podocan as a novel member of the SLRP family is implicated in the regulation of the arterial response to injury process. Mice homozygous for the podocan knockout genotype with complete deficiency in the podocan gene showed a strong and selective increase in neointima formation with no significant effect on the outer arterial wall architecture. This observation points to a specific growth inhibitory/controlling effect of podocan on highly activated intimal smooth muscle cells. However, further studies are necessary to determine the mechanism of podocan-mediated regulation of neointimal growth and to discriminate between local and systemic effects of the podocan knockout genotype.