Abstract
BackgroundJAK2/STAT3 pathway was reported to play an essential role in the neointima formation after vascular intima injury. However, little is known regarding this pathway to the whole layer injury after end-to-end arterial anastomosis (AA). Here, we investigated the role of JAK2/STAT3 pathway in common carotid arterial (CCA) anastomosis-induced cell proliferation, phenotypic change of vascular smooth muscle cells (VSMCs) and re-endothelialization.MethodsCCAs of adult male Wistar rats were resected at 3, 7, 14, and 30 days after end-to-end CCA anastomosis. Activation of JAK2/STAT3 pathway was detected by Western blotting and Immunofluorescence, and expression of proliferating cell nuclear antigen (PCNA) was detected by Q-PCR and Western blotting. Under the treatment with AG490 (a JAK2 inhibitor), protein levels of JAK2, STAT3 and PCNA, morphological changes of artery, phenotypic change of VSMCs, and re-endothelialization were measured by Western blotting, H&E, Q-PCR, and Evans blue staining respectively.ResultsThe protein levels of p-JAK2, p-STAT3, and PCNA were up-regulated, peaked on the 7th day in the vessel wall after AA. AG490 down-regulated the levels of p-JAK2, p-STAT3, and PCNA on the 7th-day-group, resulting in reduced vessel wall proliferation on the 7th and 14th day after AA. Besides, AG490 switched the phenotypic change of VSMCs after AA representing inhibited mRNA levels of synthetic phase markers (osteopoitin and SMemb) and up-regulated contractile phase markers (ASMA, SM2 and SM22α). Furthermore, AG490 did not affect the re-endothelialization process on all indicated time points after AA (the 3rd, 7th, 14th, and 30th day).ConclusionOur study indicated that JAK2/STAT3 signaling pathway played an important role on cell proliferation of the injured vessel wall, and probably a promising target for the exploration of drugs increasing the patency or reducing the vascular narrowness after AA.
Highlights
After the first human cerebral arterial anastomosis (AA) performed by Dr Yasargil in 1967 connecting superficial temporal artery (STA) to middle cerebral artery (MCA), progressions in diagnostic methods and surgical techniques have led to a revival of cerebral revascularization procedures
We studied the functional role of JAK2/STAT3 pathway in cell proliferation, vascular smooth muscle cells (VSMCs) phenotypic modulation, and re-endothelialization after AA with the hope of finding out the potential molecular mechanism underlying AA-induced cell proliferation and vascular restenosis
There is no significant difference of body temperature, body weight, and mean arterial blood pressure detected in any experimental group
Summary
After the first human cerebral arterial anastomosis (AA) performed by Dr Yasargil in 1967 connecting superficial temporal artery (STA) to middle cerebral artery (MCA), progressions in diagnostic methods and surgical techniques have led to a revival of cerebral revascularization procedures. Cytokines or growth factors firstly bind to their own receptors on the cell surface, which recruits and activates the receptor-associated JAKs. Activated JAKs phosphorylate the tyrosine residues of the specific receptors, which could be recognized by the SH2 domains of STATs. STATs form the STAT homo- or hetero-dimers, and translocate into the nucleus, where they bind to specific DNA elements and modulate the expression of target genes [5,6]. STATs form the STAT homo- or hetero-dimers, and translocate into the nucleus, where they bind to specific DNA elements and modulate the expression of target genes [5,6] Inhibition of this pathway attenuated the neointima formation and cell proliferation after common carotid arteries (CCA) intima injury in previous studies [7,8]. We investigated the role of JAK2/STAT3 pathway in common carotid arterial (CCA) anastomosis-induced cell proliferation, phenotypic change of vascular smooth muscle cells (VSMCs) and re-endothelialization
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