Apoptosis, cell proliferation and modulation of cyclin-dependent kinase inhibitor p21(cip1) in vascular remodelling during vein arterialization in the rat.
Neo-intima development and atherosclerosis limit long-term vein graft use for revascularization of ischaemic tissues. Using a rat model, which is technically less challenging than smaller rodents, we provide evidence that the temporal morphological, cellular, and key molecular events during vein arterialization resemble the human vein graft adaptation. Right jugular vein was surgically connected to carotid artery and observed up to 90 days. Morphometry demonstrated gradual thickening of the medial layer and important formation of neo-intima with deposition of smooth muscle cells (SMC) in the subendothelial layer from day 7 onwards. Transmission electron microscopy showed that SMCs switch from the contractile to synthetic phenotype on day 3 and new elastic lamellae formation occurs from day 7 onwards. Apoptosis markedly increased on day 1, while alpha-actin immunostaining for SMC almost disappeared by day 3. On day 7, cell proliferation reached the highest level and cellular density gradually increased until day 90. The relative magnitude of cellular changes was higher in the intima vs. the media layer (100 vs. 2 times respectively). Cyclin-dependent kinase inhibitors (CDKIs) p27(Kip1) and p16(INKA) remained unchanged, whereas p21(Cip1) was gradually downregulated, reaching the lowest levels by day 7 until day 90. Taken together, these data indicate for the first time that p21(Cip1) is the main CDKI protein modulated during the arterialization process the rat model of vein arterialization that may be useful to identify and validate new targets and interventions to improve the long-term patency of vein grafts.
Borin
Thaiz Ferraz
TF
Laboratory of Genetic and Molecular Cardiology/LIM-13, Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, SP, Brazil.
Miyakawa
Ayumi Aurea
AA
Cardoso
Leandro
L
de Figueiredo Borges
Luciano
L
Gonçalves
Giovana Aparecida
GA
Krieger
Jose Eduardo
JE
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001166:Arteriovenous Shunt, Surgical; D017536:Carotid Artery, Common / Q000601:surgery; D049109:Cell Proliferation; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007601:Jugular Veins / Q000378:metabolism / Q000601:surgery / Q000637:transplantation* / Q000648:ultrastructure; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000199:Actins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21