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Thomas Doetschman

Publications and source records attributed to Thomas Doetschman.

At least 19 recordsLinked to original sources
PubMed2006

Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 Na+/HCO3- cotransporter.

The NBC1 Na+/HCO3- cotransporter is expressed in many tissues, including kidney and intestinal epithelia. NBC1 mutations cause proximal renal tubular acidosis in humans, consistent with its role in HCO3- absorption in the kidney. In intestinal and colonic epithelia, NBC1 localizes to basolateral membranes and is thought to function in anion secretion. To test the hypothesis that NBC1 plays a role in transepithelial HCO3- secretion in the intestinal tract, null mutant (NBC1-/-) mice were prepared by targeted disruption of its gene (Slc4a4). NBC1-/- mice exhibited severe metabolic acidosis, growth retardation, reduced plasma Na+, hyperal-dosteronism, splenomegaly, abnormal dentition, intestinal obstructions, and death before weaning. Intracellular pH (pH(i)) was not altered in cAMP-stimulated epithelial cells of NBC1-/- cecum, but pH(i) regulation during sodium removal and readdition was impaired. Bioelectric measurements of NBC1-/- colons revealed increased amiloride-sensitive Na+ absorption. In Ringer solution containing both Cl- and HCO3-, the magnitude of cAMP-stimulated anion secretion was normal in NBC1-/- distal colon but increased in proximal colon, with the increase largely supported by enhanced activity of the basolateral NKCC1 Na+-K+-2Cl- cotransporter. Anion substitution studies in which carbonic anhydrase was inhibited and transepithelial anion conductance was limited to HCO3- revealed a sharp decrease in both cAMP-stimulated HCO3- secretion and SITS-sensitive current in NBC1-/- proximal colon. These results are consistent with the known function of NBC1 in HCO3- absorption in the kidney and demonstrate that NBC1 activity is a component of the basolateral mechanisms for HCO3- uptake during cAMP-stimulated anion secretion in the proximal colon.

Acidosis↗
PubMed2006

The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: the role of JNK signaling.

UNLABELLED: Our laboratory showed that overexpression of fibroblast growth factor-2 (FGF2) protected the heart against ischemia-reperfusion injury. FGF2 has different protein isoforms (low [LMW] and high [HMW] molecular weight isoforms) produced from alternative translation start sites. However, which FGF2 isoform(s) mediates this cardioprotection, and which signaling pathway (i.e., mitogen-activated protein kinase (MAPK)) elicits FGF2 isoform-induced cardioprotection remains to be elucidated. METHODS AND RESULTS: Wildtype, Fgf2 KO (absence of all FGF2 isoforms) and FGF2 LMWKO (absence of LMW isoform) hearts were subjected to an ex vivo work-performing heart ischemic model of 60 min ischemia and 120 min reperfusion. There was a significant decrease in the recovery of post-ischemic contractile function (p<0.05) in Fgf2 KO and FGF2 LMWKO mouse hearts compared to wildtype hearts. Following ischemia-reperfusion injury, MKK4/7, JNK, and c-Jun were significantly phosphorylated (i.e., activated), and the levels of TUNEL-positive nuclei and caspase 3 cleavage were significantly increased in vehicle-treated Fgf2 KO and FGF2 LMWKO compared to wildtype hearts (p<0.05). A novel JNK pathway inhibitor, CEP11004 (50 nM), significantly restored the post-ischemic contractile function and reduced myocardial cell death, as measured by CK release and apoptotic markers, compared to DMSO-treated cohorts (p<0.05). Overall, our data indicate that the LMW isoform has an important role in restoring cardiac function after ischemia-reperfusion (I/R) injury. These results provide unequivocal evidence that inhibition of JNK signaling is involved in FGF2 LMW isoform-mediated cardioprotection and that the potential mechanism may be through inhibition of the apoptotic process.

Animals↗
PubMed2006

Self-antigen recognition by TGF beta1-deficient T cells causes their activation and systemic inflammation.

To investigate whether the multifocal inflammatory disease in TGFbeta1-deficient mice is caused by self-antigen (self-Ag)-specific autoreactive T cells, or whether it is caused by antigen independent, spontaneous hyperactivation of T cells, we have generated Tgfb1(-/-) and Tgfb1(-/-) Rag1(-/-) mice expressing the chicken OVA-specific TCR transgene (DO11.10). On a Rag1-sufficient background, Tgfb1(-/-) DO11.10 mice develop a milder inflammation than do Tgfb1(-/-) mice, and their T cells display a less activated phenotype. The lower level of activation correlates with the expression of hybrid TCR (transgenic TCRbeta and endogenous TCRalpha), which could recognize self-Ag and undergo activation. In the complete absence of self-Ag recognition (Tgfb1(-/-) DO11.10 Rag1(-/-) mice) inflammation and T-cell activation are eliminated, demonstrating that self-Ag recognition is required for the hyper-responsiveness of TGFbeta1-deficient T cells. Thus, TGFbeta1 is required for the prevention of autoimmune disease through its ability to control the activation of autoreactive T cells to self-Ag.

Animals↗
PubMed2006

Essential role of bone marrow fibroblast growth factor-2 in the effect of estradiol on reendothelialization and endothelial progenitor cell mobilization.

17beta-Estradiol (E2) accelerates reendothelialization and increases the number of circulating endothelial progenitor cells (EPCs), but whether fibroblast growth factor-2 (FGF2) is involved in these processes remains unknown. Here we explored the role of FGF2 in the effect of E2 on reendothelialization and EPC levels in a mouse model. As previously reported, E2 increased both the velocity of reendothelialization and the number of circulating EPCs in ovariectomized wild-type (Fgf2+/+) mice. In contrast, the effect of E2 on both parameters was abolished in FGF2-deficient mice (Fgf2-/-), demonstrating that FGF2 is absolutely required for these effects of E2. To test the implication of medullary and extramedullary FGF2, we developed chimeric mice by grafting Fgf2-/- bone marrow to Fgf2+/+ [Fgf2-/- bone marrow (BM) = > Fgf2+/+] mice and observed that the effect of E2 on both reendothelialization and EPC levels was abolished. In contrast, both effects of E2 in Fgf2+/+BM = >Fgf2-/- mice were similar to those observed in Fgf2+/+ mice, demonstrating that only BM-derived, but not extramedullary, FGF2 is required for both effects. Interestingly, E2 was found to markedly increase both FGF2(lmw) and FGF2(hmw) in bone marrow. In conclusion, FGF2, specifically medullary FGF2, is necessary and sufficient to mediate the accelerative effect of E2 on both reendothelialization and EPC mobilization.

Animals↗
PubMed2005

Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade.

Our laboratory showed previously that cardiac-specific overexpression of FGF-2 [FGF-2 transgenic (Tg)] results in increased recovery of contractile function and decreased infarct size after ischemia-reperfusion injury. MAPK signaling is downstream of FGF-2 and has been implicated in other models of cardioprotection. Treatment of FGF-2 Tg and wild-type hearts with U-0126, a MEK-ERK pathway inhibitor, significantly reduced recovery of contractile function after global low-flow ischemia-reperfusion injury in FGF-2 Tg (86 +/- 2% vehicle vs. 66 +/- 4% U-0126; P < 0.05) but not wild-type (61 +/- 7% vehicle vs. 67 +/- 7% U-0126) hearts. Similarly, MEK-ERK inhibition significantly increased myocardial infarct size in FGF-2 Tg (12 +/- 3% vehicle vs. 31 +/- 2% U-0126; P < 0.05) but not wild-type (30 +/- 4% vehicle vs. 36 +/- 7% U-0126) hearts. In contrast, treatment of FGF-2 Tg and wild-type hearts with SB-203580, a p38 inhibitor, did not abrogate FGF-2-induced cardioprotection from postischemic contractile dysfunction. Instead, inhibition of p38 resulted in decreased infarct size in wild-type hearts (30 +/- 4% vehicle vs. 11 +/- 2% SB-203580; P < 0.05) but did not alter infarct size in FGF-2 Tg hearts (12 +/- 3% vehicle vs. 14 +/- 1% SB-203580). Western blot analysis of ERK and p38 activation revealed signaling alterations in FGF-2 Tg and wild-type hearts during early ischemia or reperfusion injury. In addition, MEK-independent ERK inhibition by p38 was observed during early ischemic injury. Together these data suggest that activation of ERK and inhibition of p38 by FGF-2 is cardioprotective during ischemia-reperfusion injury.

Animals↗
PubMed2005

Elimination of both CD4+ and CD8+ T cells but not B cells eliminates inflammation and prolongs the survival of TGFbeta1-deficient mice.

Transforming growth factor beta1 (TGFbeta1) is a potent negative immunoregulatory molecule. We have previously shown that the autoimmune-mediated weaning-age lethality of Tgfb1-/- mice is reversed upon genetic combination with Scid or Rag null alleles. Here, we show that elimination of T but not B cells is sufficient for the reversal, but elimination of either CD4+ or CD8+ cells is not. Although elimination of B cells does not rescue TGFbeta1-deficient animals from autoimmunity, B cells are hyperresponsive to LPS in the absence of TGFbeta1. TGFbeta1 deficiency leads to activation of CD8+ T cells as suggested by down-modulation of CD8 even in the absence of CD4+ T cells. This study provides evidence that both CD4+ and CD8+ T cells, but not B cells, have the ability to cause inflammation in the absence of TGFbeta1. However, though TGFbeta1-deficient B cells are hyperresponsive to stimulation, alone they are not sufficient to cause inflammation.

Animals↗
PubMed2005

Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 Na+/H+ exchanger.

The NHE4 Na+/H+ exchanger is abundantly expressed on the basolateral membrane of gastric parietal cells. To test the hypothesis that it is required for normal acid secretion, NHE4-null mutant (NHE4-/-) mice were prepared by targeted disruption of the NHE4 (Slc9a4) gene. NHE4-/- mice survived and appeared outwardly normal. Analysis of stomach contents revealed that NHE4-/- mice were hypochlorhydric. The reduction in acid secretion was similar in 18-day-old, 9-week-old, and 6-month-old mice, indicating that the hypochlorhydria phenotype did not progress over time, as was observed in mice lacking the NHE2 Na+/H+ exchanger. Histological abnormalities were observed in the gastric mucosa of 9-week-old NHE4-/- mice, including sharply reduced numbers of parietal cells, a loss of mature chief cells, increased numbers of mucous and undifferentiated cells, and an increase in the number of necrotic and apoptotic cells. NHE4-/- parietal cells exhibited limited development of canalicular membranes and a virtual absence of tubulovesicles, and some of the microvilli had centrally bundled actin. We conclude that NHE4, which may normally be coupled with the AE2 Cl-/HCO3- exchanger, is important for normal levels of gastric acid secretion, gastric epithelial cell differentiation, and development of secretory canalicular and tubulovesicular membranes.

Achlorhydria↗
PubMed2004

Transforming growth factor beta-SMAD2 signaling regulates aortic arch innervation and development.

Aortic arch interruptions in humans and animal models are mainly caused by aberrant development of the fourth pharyngeal arch artery. Little is known about the maturation of this vessel during normal and abnormal development, which is the subject of this study. Tgfbeta2 knockout mice that present with fourth artery defects have been associated with defective neural crest cell migration. In this study, we concentrated on pharyngeal arch artery development during developmental days 12.5 to 18.5, focusing on neural crest cell migration using a Wnt1-Cre by R26R neural crest cell reporter mouse. Fourth arch artery maturation was studied with antibodies directed against smooth muscle alpha-actin and neural NCAM-1 and RMO-270. For diminished transforming growth factor beta (TGF-beta) signaling, SMAD2 and fibronectin have been analyzed. Neural crest migration and differentiation into smooth muscle cells is unaltered in mutants, regardless of the cardiovascular defect found; however, innervation of the fourth arch artery is affected. Absent staining for nuclear SMAD2, NCAM-1, and RMO-270 in the fourth artery in mutant coincides with severe defects of this segment. Likewise, fibronectin expression is diminished in these cases. From these data we conclude the following: (1) neural crest cell migration is not a common denominator in cardiovascular defects of Tgfbeta2-/- mice; (2) fourth arch artery maturation is a complex process involving innervation; and (3) TGF-beta2 depletion diminishes SMAD2-signaling in the fourth arch artery and coincides with reduced vascular NCAM-1 expression and neural innervation of this artery. We hypothesize that disturbed maturation of the fourth pharyngeal arch artery, and especially abrogated vascular innervation, will result in fourth arch interruptions.

Abnormalities, Multiple↗
PubMed2004

Targeted ablation of plasma membrane Ca2+-ATPase (PMCA) 1 and 4 indicates a major housekeeping function for PMCA1 and a critical role in hyperactivated sperm motility and male fertility for PMCA4.

The relative importance of plasma membrane Ca2+-ATPase (PMCA) 1 and PMCA4 was assessed in mice carrying null mutations in their genes (Atp2b1 and Atp2b4). Loss of both copies of the gene encoding PMCA1 caused embryolethality, whereas heterozygous mutants had no overt disease phenotype. Despite widespread and abundant expression of PMCA4, PMCA4 null (Pmca4-/-) mutants exhibited no embryolethality and appeared outwardly normal. Loss of PMCA4 impaired phasic contractions and caused apoptosis in portal vein smooth muscle in vitro; however, this phenotype was dependent on the mouse strain being employed. Pmca4-/- mice on a Black Swiss background did not exhibit the phenotype unless they also carried a null mutation in one copy of the Pmca1 gene. Pmca4-/- male mice were infertile but had normal spermatogenesis and mating behavior. Pmca4-/- sperm that had not undergone capacitation exhibited normal motility but could not achieve hyperactivated motility needed to traverse the female genital tract. Ultrastructure of the motility apparatus in Pmca4-/- sperm tails was normal, but an increased incidence of mitochondrial condensation indicated Ca2+ overload. Immunoblotting and immunohistochemistry showed that PMCA4 is the most abundant isoform in testis and sperm and that it is localized to the principle piece of the sperm tail, which is also the location of the major Ca2+ channel (CatSper) required for sperm motility. These results are consistent with an essential housekeeping or developmental function for PMCA1, but not PMCA4, and show that PMCA4 expression in the principle piece of the sperm tail is essential for hyperactivated motility and male fertility.

Alleles↗
PubMed2004

Mice with a targeted disruption of the AE2 Cl-/HCO3- exchanger are achlorhydric.

The AE2 Cl-/HCO3- exchanger is expressed in numerous cell types, including epithelial cells of the kidney, respiratory tract, and alimentary tract. In gastric epithelia, AE2 is particularly abundant in parietal cells, where it may be the predominant mechanism for HCO3- efflux and Cl- influx across the basolateral membrane that is needed for acid secretion. To investigate the hypothesis that AE2 is critical for parietal cell function and to assess its importance in other tissues, homozygous null mutant (AE2(-/-)) mice were prepared by targeted disruption of the AE2 (Slc4a2) gene. AE2(-/-) mice were emaciated, edentulous (toothless), and exhibited severe growth retardation, and most of them died around the time of weaning. AE2(-/-) mice exhibited achlorhydria, and histological studies revealed abnormalities of the gastric epithelium, including moderate dilation of the gastric gland lumens and a reduction in the number of parietal cells. There was little evidence, however, that parietal cell viability was impaired. Ultrastructural analysis of AE2(-/-) gastric mucosa revealed abnormal parietal cell structure, with severely impaired development of secretory canaliculi and few tubulovesicles but normal apical microvilli. These results demonstrate that AE2 is essential for gastric acid secretion and for normal development of secretory canalicular and tubulovesicular membranes in mouse parietal cells.

Achlorhydria↗
PubMed2003

Cardiac-specific overexpression of fibroblast growth factor-2 protects against myocardial dysfunction and infarction in a murine model of low-flow ischemia.

BACKGROUND: Preconditioning the heart before an ischemic insult has been shown to protect against contractile dysfunction, arrhythmias, and infarction. Pharmacological studies have suggested that fibroblast growth factor-2 (FGF2) is involved in cardioprotection. However, because of the number of FGFs expressed in the heart and the promiscuity of FGF ligand-receptor interactions, the specific role of FGF2 during ischemia-reperfusion injury remains unclear. METHODS AND RESULTS: FGF2-deficient (Fgf2 knockout) mice and mice with a cardiac-specific overexpression of all 4 isoforms of human FGF2 (FGF2 transgenic [Tg]) were compared with wild-type mice to test whether endogenous FGF2 elicits cardioprotection. An ex vivo work-performing heart model of ischemia was developed in which murine hearts were subjected to 60 minutes of low-flow ischemia and 120 minutes of reperfusion. Preischemic contractile function was similar among the 3 groups. After ischemia-reperfusion, contractile function of Fgf2 knockout hearts recovered to 27% of its baseline value compared with a 63% recovery in wild-type hearts (P<0.05). In FGF2 Tg hearts, an 88% recovery of postischemic function occurred (P<0.05). Myocardial infarct size was also reduced in FGF2 Tg hearts compared with wild-type hearts (13% versus 30%, P<0.05). There was a 2-fold increase in FGF2 release from Tg hearts compared with wild-type hearts (P<0.05). No significant alterations in coronary flow or capillary density were detected in any of the groups, implying that the protective effect of FGF2 is not mediated by coronary perfusion changes. CONCLUSIONS: These results provide evidence that endogenous FGF2 plays a significant role in the cardioprotective effect against ischemia-reperfusion injury.

Animals↗
PubMed2003

Protein tyrosine phosphatase alpha (PTP alpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety.

Receptor PTPalpha is a widely expressed transmembrane enzyme enriched in brain. PTPalpha knockout (PTPalpha(-/-)) mice are viable and display no gross abnormalities. Brain and embryo derived fibroblast src and fyn activity is reduced to <50% in PTPalpha(-/-) mice. These protein kinases are implicated in multiple aspects of neuronal development and function. However, the effect of the loss of function of the PTPalpha gene on behavior has yet to be investigated. PTPalpha(-/-) and WT mice were tested for anxiety, swimming ability, spatial learning, cued learning, locomotor activity, and novel object recognition (NOR). PTPalpha(-/-) mice were indistinguishable from WT in swimming ability, cued learning and novel object recognition. Knockout mice showed decreased anxiety without an increase in head dips and stretch-attend movements. During Morris water maze (MWM) learning, PTPalpha(-/-) mice had increased latencies to reach the goal compared to WT on acquisition, but no memory deficit on probe trials. On reversal learning, knockout mice showed no significant effects. PTPalpha(-/-) mice showed decreased exploratory locomotor activity, but responded normally to a challenge dose of D-methamphetamine. The data suggest that PTPalpha serves a regulatory function in learning and other forms of neuroplasticity.

Animals↗
PubMed2003

TGF-beta 1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes.

TGF-beta1 plays an important role in the maintenance of immune homeostasis and self-tolerance. To determine the mechanism by which TGF-beta1 prevents autoimmunity we have analyzed T cell activation in splenic lymphocytes from TGF-beta1-deficient mice. Here we demonstrate that unlike wild-type splenic lymphocytes, those from Tgfb1(-/-) mice are hyporesponsive to receptor-mediated mitogenic stimulation, as evidenced by diminished proliferation and reduced IL-2 production. However, they have elevated levels of IFN-gamma and eventually undergo apoptosis. Receptor-independent stimulation of Tgfb1(-/-) T cells by PMA plus ionomycin induces IL-2 production and mitogenic response, and it rescues them from anergy. Tgfb1(-/-) T cells display decreased CD3 expression; increased expression of the activation markers LFA-1, CD69, and CD122; and increased cell size, all of which indicate prior activation. Consistently, mutant CD4(+) T cells have elevated intracellular Ca(2+) levels. However, upon subsequent stimulation in vitro, increases in Ca(2+) levels are less than those in wild-type cells. This is also consistent with the anergic phenotype. Together, these results demonstrate that the ex vivo proliferative hyporesponsiveness of Tgfb1(-/-) splenic lymphocytes is due to prior in vivo activation of T cells resulting from deregulated intracellular Ca(2+) levels.

Animals↗
PubMed2003

TGF beta 1 inhibits Ca2+-calcineurin-mediated activation in thymocytes.

TGFbeta1 is a polypeptide growth modulatory and differentiation factor involved in many biological processes including immune homeostasis and self-tolerance. Tgfb1 knockout mice die around weaning age due to severe inflammation in most major organ systems, but the mechanism underlying this disease is not understood. In this study we demonstrate that Tgfb1(-/-) CD4(+)CD8(+) and CD4(+)CD8(-) thymocytes are hyperresponsive to receptor-mediated and receptor-independent mitogenic stimulation. A suboptimal concentration of ionomycin in the presence of PMA fully activates Tgfb1(-/-) thymocytes, whereas the inhibitors of Ca(2+) influx and calcineurin, EGTA and FK506, eliminate the hyperresponsiveness. Hence, the hypersensitivity of Tgfb1(-/-) thymocytes is due to a lowered threshold for Ca(2+)-dependent activation. Further, we demonstrate that the hypersensitivity of thymocytes results from the absence of TGFbeta1 and not from the inflammatory environment because the thymocytes are hyperresponsive in preinflammatory-stage Tgfb1(-/-) mice. Our results suggest for the first time that TGFbeta1 functions to inhibit aberrant T cell expansion by maintaining intracellular calcium concentration levels low enough to prevent a mitogenic response by Ca(2+)-independent stimulatory pathways alone. Consequently, TGFbeta1 prevents autoimmune disease through a Ca(2+) regulatory pathway that maintains the activation threshold above that inducible by self-MHC-TCR interactions.

Animals↗
PubMed2003

Impaired osteoclast formation in bone marrow cultures of Fgf2 null mice in response to parathyroid hormone.

Fibroblast growth factor (FGF)-2 and parathyroid hormone (PTH) are potent inducers of osteoclast (OCL) formation, and PTH increases FGF-2 mRNA and protein expression in osteoblasts. To elucidate the role of endogenous FGF-2 in PTH responses, we examined PTH-induced OCL formation in bone marrow cultures from wild type and mice with a disruption of the Fgf2 gene. FGF-2-induced OCL formation was similar in marrow culture from both genotypes. In contrast, PTH-stimulated OCL formation in bone marrow cultures or co-cultures of osteoblast-spleen cells from Fgf2-/mice was significantly impaired. PTH increased RANKL mRNA expression in osteoblasts cultures from both genotypes. After 6 days of treatment, osteoprotegerin protein in cell supernatants was 40-fold higher in vehicle-treated and 30-fold higher in PTH-treated co-cultures of osteoblast and spleen cells from Fgf2-/mice compared with Fgf2+/+ mice. However, a neutralizing antibody to osteoprotegerin did not rescue reduced OCL formation in response to PTH. Injection of PTH caused hypercalcemia in Fgf2+/+ but not Fgf2-/mice. We conclude that PTH stimulates OCL formation and bone resorption in mice in part by endogenous FGF-2 synthesis by osteoblasts. Because RANKL- and interleukin-11-induced OCL formation was also reduced in bone marrow cultures from Fgf2-/mice, we further conclude that endogenous FGF-2 is necessary for maximal OCL formation by multiple bone resorbing factors.

Acid Phosphatase↗
PubMed2003

Transforming growth factor beta in cardiovascular development and function.

Transforming growth factor betas (TGFbetas) are pleiotropic cytokines involved in many biological processes. Genetic engineering and tissue explanation studies have revealed specific non-overlapping roles for TGFbeta ligands and their signaling molecules in development and in normal function of the cardiovascular system in the adult. In the embryo, TGFbetas appear to be involved in epithelial-mesenchymal transformations (EMT) during endocardial cushion formation, and in epicardial epithelial-mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. In the adult, TGFbetas are involved in cardiac hypertrophy, vascular remodeling and regulation of the renal renin-angiotensin system. The evidence for TGFbeta activities during cardiovascular development and physiologic function will be given and areas which need further investigation will be discussed.

Animals↗
PubMed2002

Targeted disruption of the Fgf2 gene does not affect vascular growth in the mouse ischemic hindlimb.

Ischemic revascularization involves extensive structural adaptation of the vasculature, including both angiogenesis and arteriogenesis. Previous studies suggest that fibroblast growth factor (FGF)-2 participates in both angiogenesis and arteriogenesis. Despite this, the specific role of endogenous FGF-2 in vascular adaptation during ischemic revascularization is unknown. Therefore, we used femoral artery ligation in Fgf2(+/+) and Fgf2(-/-) mice to test the hypothesis that endogenous FGF-2 is an important regulator of angiogenesis and arteriogenesis in the setting of hindlimb ischemia. Femoral ligation increased capillary and arteriole density in the ischemic calf in both Fgf2(+/+) and Fgf2(-/-) mice. The level of angiographically visible arteries in the thigh was increased in the ischemic hindlimb in all mice, and no significant differences were observed between Fgf2(+/+) and Fgf2(-/-) mice. Additionally, limb perfusion progressively improved to peak values at day 35 postsurgery in both genotypes. Given the equivalent responses observed in Fgf2(+/+) and Fgf2(-/-) mice, we demonstrate that endogenous FGF-2 is not required for revascularization in the setting of peripheral ischemia. Vascular adaptation, including both angiogenesis and arteriogenesis, was not affected by the absence of FGF-2 in this model.

Animals↗