title: Focal adhesion kinase regulates smooth muscle cell recruitment to the developing vasculature.
abstract: OBJECTIVE
  The investment of newly formed endothelial cell tubes with differentiated smooth muscle cells (SMC) is critical for appropriate vessel formation, but the underlying mechanisms remain unknown. We previously showed that depletion of focal adhesion kinase (FAK) in the nkx2.5 expression domain led to aberrant outflow tract (OFT) morphogenesis and strove herein to determine the cell types and mechanisms involved.
  
  
  RESULTS
  We crossed fak(loxp) targeted mice with available Cre drivers to deplete FAK in OFT SMC (FAK(wnt) and FAK(nk)) or coronary SMC (FAK(cSMC)). In each case, depletion of FAK led to defective vasculogenesis that was incompatible with postnatal life. Immunohistochemical analysis of the mutant vascular structures revealed that FAK was not required for progenitor cell proliferation, survival, or differentiation into SMC but was necessary for subsequent SMC recruitment to developing vasculature. Using a novel FAK-null SMC culture model, we found that depletion of FAK did not influence SMC growth or survival, but blocked directional SMC motility and invasion toward the potent endothelial-derived chemokine, platelet-derived growth factor PDGFBB. FAK depletion resulted in unstable lamellipodial protrusions due to defective spatial-temporal activation of the small GTPase, Rac-1, and lack of Rac1-dependent recruitment of cortactin (an actin stabilizing protein) to the leading edge. Moreover, FAK null SMC exhibited a significant reduction in stimulated extracellular matrix degradation.
  
  
  CONCLUSIONS
  FAK drives PDGFBB-stimulated SMC chemotaxis/invasion and is essential for SMC to appropriately populate the aorticopulmonary septum and the coronary vascular plexus.
authors.affiliation: Department of Pathology, University of North Carolina, Chapel Hill, 27599-7525, USA.
authors.forename: Zhaokang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Liisa J
authors.initials: LJ
authors.lastname: Sundberg-Smith
authors.forename: Lee E
authors.initials: LE
authors.lastname: Mangiante
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Sayers
authors.forename: Zeenat S
authors.initials: ZS
authors.lastname: Hakim
authors.forename: Srilaxmi
authors.initials: S
authors.lastname: Musunuri
authors.forename: Colin T
authors.initials: CT
authors.lastname: Maguire
authors.forename: Mark W
authors.initials: MW
authors.lastname: Majesky
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Mack
authors.forename: Joan M
authors.initials: JM
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001011:Aorta / Q000196:embryology / Q000201:enzymology; D017209:Apoptosis; D000077214:Becaplermin; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D002633:Chemotaxis / Q000235:genetics; D003331:Coronary Vessels / Q000196:embryology / Q000201:enzymology; D051356:Cortactin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000196:embryology / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D018919:Neovascularization, Physiologic / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011554:Pseudopodia / Q000201:enzymology; D011651:Pulmonary Artery / Q000196:embryology / Q000201:enzymology; D011784:Quail / Q000196:embryology; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D051356:Cortactin; C495869:Cttn protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D009479:Neuropeptides; C484469:Nkx2-5 protein, mouse; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C484602:Rac1 protein, mouse; D014157:Transcription Factors; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D000077214:Becaplermin; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein