Elastogenic inductability of smooth muscle cells from a XXXX model of late stage @entity1028 .

@entity1 @entity32 @entity1810 @entity35 @entity1028
Although @entity1028 ( @entity1028 ) can be potentially stabilized by inhibiting inflammatory cell recruitment and their release of proteolytic enzymes, active @entity1028 regression is not possible without regeneration of new elastic matrix structures. Unfortunately, postneonatal vascular smooth muscle cells (SMCs), healthy, and likely more so, diseased cells, poorly synthesize or remodel elastic fibers, impeding any effort directed at regenerative @entity1028 treatment. Previously, we determined the eleastogenic benefits of oligomers (HA-o; 4-6 mers) of the glycosaminoglycan, hyaluronan (HA) and @entity1810 ( @entity1810 ) to healthy SMCs. Since AAAs are often diagnosed only late in development when matrix disruption is severe, we now determine if elastogenic upregulation of SMCs from late-stage AAAs (>100% diameter increase) is possible. AAAs were induced by perfusion of @entity35 infrarenal aortae with porcine pancreatic elastase. Elastic matrix degradation, vessel expansion (   120%), @entity32 , and enhanced activity of matrix-metalloproteases (MMPs) 2 and 9 resulted, paralleling @entity1 AAAs. Aneurysmal SMCs (EaRASMCs) maintained a diseased phenotype in 2D cell culture and exhibited patterns of gene expression different from healthy @entity35 aortic SMCs (RASMCs). Relative to passage-matched healthy RASMCs, unstimulated EaRASMCs produced far less tropoelastin and matrix elastin. Exogenous @entity1810 and HA-o (termed "factors") significantly decreased EaRASMC proliferation and enhanced tropoelastin synthesis, though only at the highest provided dose combination (20   mg/mL of HA-o, 10   ng/mL of @entity1810 ); despite such enhancement, tropoelastin amounts were only    40% of amounts synthesized by healthy RASMC cultures. Differently, elastic matrix synthesis was enhanced beyond amounts synthesized by healthy RASMCs (112%), even at lower doses of factors (2   mg/mL of HA-o and 5   ng/mL of @entity1810 ). The factors also enhanced elastic fiber deposition over untreated EaRASMC cultures and restored several genes whose expression was altered in EaRASMC cultures back to levels expressed by healthy RASMCs. However, the activity of MMPs 2 and 9 generated by EaRASMC cultures was unaffected by the factors/factor dose. The study confirms that SMCs from advanced AAAs can be elastogenically induced, although much higher doses of elastogenic factors are required for induction relative to healthy SMCs. Also, the factors do not appear to inhibit MMP activity, vital to preserve existing elastic matrix structures that serve as nucleation sites for new elastic fiber deposition. Thus, to enhance net accumulation of newly regenerated elastic matrix, toward possibly regressing AAAs, codelivery of MMP inhibitors may be necessitated.
