Abstract
Molecular mechanisms that control the activities of vascular smooth muscle cells (VSMCs) in the diseased or injured arterial wall remain incompletely understood. The atypical cadherin FAT1 is prominently expressed in VSMCs after vascular injury. In recent work, we found that processing of FAT1, a type I transmembrane protein, releases its intracellular domain, the FAT1ICD; in turn, FAT1ICD fragments accumulate in mitochondria and interact with electron transport complexes I and II to restrict VSMC respiration and control cell growth and neointimal formation. We hypothesized that FAT1 processing (and therefore these VSMC activities) is controlled by extracellular ligands that may interact physically via FAT1’s extended cadherin repeat or transmembrane domains. FAT4 and Dachsous 1 (DCHS1) are leading candidates for such interactions, but these proteins have not been studied in VSMCs or vascular injury response. Accordingly, we analyzed expression profiles of FAT4 and Dachsous 1 (DCHS1) during the vascular response to injury, using a rat carotid artery balloon injury model. Interestingly, FAT4 transcripts increased transiently after injury, peaking at day 7 (6.99±0.21-fold over baseline, P<.001), in a pattern reminiscent of FAT1. In contrast, DCHS1 levels decreased by day 3 after injury (0.49±0.02-fold of baseline, P<.001), remained low through day 14, and recovered by day 30. Physical interactions of FAT4 either with DCHS1 or with FAT1 have both been reported previously; therefore, decreased DCHS1 coincident with increased FAT4 suggest an increase in FAT4 availability and/or interaction with FAT1 during injury response. How this increase in FAT4 affects FAT1 function and VSMC metabolism and growth is the subject of ongoing investigation. FAT1 induction and processing after vascular injury represent an important novel molecular mechanism by which VSMC metabolism and growth are controlled after vascular injury. Increased availability of FAT4 cadherin due to FAT4 induction together with DCHS1 downregulation after vascular injury provides a likely upstream regulatory mechanism to govern FAT1 activities.
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