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. 2015 Dec;14(6):1034-44.
doi: 10.1111/acel.12372. Epub 2015 Jul 14.

IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

Peter Toth  1   2 , Stefano Tarantini  1   3 , Nicole M Ashpole  1 , Zsuzsanna Tucsek  1 , Ginger L Milne  4 , Noa M Valcarcel-Ares  1 , Akos Menyhart  5 , Eszter Farkas  5 , William E Sonntag  1   6 , Anna Csiszar  1   2   3   6 , Zoltan Ungvari  1   2   3   6   7
Affiliations

IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

Peter Toth et al. Aging Cell. 2015 Dec.

Abstract

Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.

Keywords: Insulin-like growth factor-1; arachidonic acid metabolites; astrocyte; endothelial dysfunction; functional hyperemia; neurovascular uncoupling; nitric oxide; somatomedin C; vascular aging; vascular cognitive impairment.

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Figures

Figure 1
Figure 1
IGF‐1 deficiency impairs neurovascular coupling and cognitive function. Panel A shows that adeno‐associated viral knockdown of hepatic Igf1 (Igf1 f/f + TBG‐Cre‐AAV8) decreases significantly the level of circulating IGF‐1 compared to control animals (Igf1 f/f + TBG‐eGFP‐AAV8) (*P < 0.05 vs. control). (B) Representative traces of cerebral blood flow (CBF) measured with a laser Doppler probe above the whisker barrel cortex during contralateral whisker stimulation (5 Hz) in control and IGF‐1‐deficient mice. 1 AU corresponds to ~5% increase in CBF from baseline. Right panel depicts the summary data of the CBF responses (ΔAUC as % of baseline; n = 12, *P < 0.001 vs. control). (C–D) Spontaneous and evoked neural activity is not altered in IGF‐1‐deficient mice. (C) The amplitude and frequency distribution of neocortical electrical activity are nearly identical in control and IGF‐1‐deficient mice (inlet shows original recording of electrocorticograms, n = 6, P = 0.4). (D) The somatosensory evoked potential (SEP) responses in the somatosensory cortex evoked by contralateral whisker pad stimulation are comparable in control and IGF‐1‐deficient mice. The arrow indicates the application of the stimulus. The amplitude of the negative wave of the field potentials (N1) does not differ between control and IGF‐1‐deficient mice (n = 6, P = 0.6). (E–F) Spatial memory testing of mice in Y‐maze. The IGF‐1‐deficient animals (Igf1 f/f + TBG‐Cre‐AAV8) exhibited impaired spatial memory as shown by the decreased number of entries in novel arm (E; * P = 0.001 vs. control) and shorter exploratory time spent in novel arm of the Y‐maze during retrieval trial (F; and P = 0.01 vs. control). Data are mean ± S.E.M., n = 20 in each group.
Figure 2
Figure 2
IGF‐1 deficiency impairs cerebromicrovascular endothelial function: role in neurovascular uncoupling. (A) L‐NAME‐sensitive, NO‐mediated portion of the CBF response (calculated based on the percentage decline in CBF in the presence of L‐NAME) measured above the barrel field of the primary somatosensory cortex in response to whisker stimulation in control and IGF‐1‐deficient (Igf1 f/f + TBG‐Cre‐AAV8) mice (n = 6, * P < 0.05 vs. control; # P < 0.05 vs. control w/o drug; & P < 0.05 vs. Igf1 f/f + TBG‐Cre‐AAV8 w/o drug). (B) CBF responses elicited by topical administration of acetylcholine to the barrel field of control and IGF‐1‐deficient mice (n = 6, *P < 0.05 vs. control). (C) Protein 3‐nitrotyrosine content, a biomarker of increased ONOO‐ formation, in cortical tissue of IGF‐1‐deficient and control mice (n = 5, *P < 0.05 vs. control). (D) qPCR data showing mRNA expression of the endothelial nitric oxide synthase (Nos3) and the NADPH oxidase subunits Nox1, Nox2, and Nox4 in cortical samples of IGF‐1‐deficient and control mice. Data are mean ± S.E.M. (n = 5, *P < 0.05 vs. control).
Figure 3
Figure 3
IGF‐1 deficiency impairs glutamate‐mediated CBF responses: role in neurovascular uncoupling. (A) Effects of treatment with antagonists of metabotropic glutamate receptors (MPEP, 5 × 10−5 mol L−1) and NMDA receptors (N‐methyl‐D‐aspartate, D‐APV, 5 × 10−5 mol L−1) on cerebral blood flow (CBF) responses measured above the barrel field of the primary somatosensory cortex in response to whisker stimulation in control and IGF‐1‐deficient mice (Igf1 f/f + TBG‐Cre‐AAV8). The inlet shows the glutamate‐mediated part of the neurovascular response in each group (n = 6 in each group, *P < 0.05 vs. control; # P < 0.05 vs. Igf1 f/f + TBG‐Cre‐AAV8). (B) CBF responses measured above the barrel field of the primary somatosensory cortex elicited by topical administration of L‐glutamate (500 μmol L−1) in control and IGF‐1‐deficient mice (n = 6 in each group, *P < 0.05 vs. control). Panel C Original recordings of changes in extracellular glutamate in response to whisker stimulation (5 Hz, 2 min) measured by amperometry using a glutamate biosensor inserted into the barrel cortex of mice (see Methods for details). ‘Null sensor’ indicates a biosensor constructed the same way as the glutamate sensors but without any enzymes for biosensing. Summary data are shown in Panel D. No significant differences (P = 0.4) were observed between cortical glutamate signals induced by whisker stimulation in control (n = 5) and IGF‐1‐deficient mice (Igf1 f/f + TBG‐Cre‐AAV8, n = 7). (E) qPCR data showing mRNA expression of NMDA receptors (Grin1, Grin2A, Grin2B), metabotropic glutamate receptors (Grm1, Grm2, Grm3, Grm4, Grm5), and glutamate transporters (Slc1a1, Slc1a2) on astrocytes isolated from control and IGF‐1‐deficient animals (n = 5). *P < 0.05 vs. control. Data are mean ± S.E.M. for every panel of the figure.
Figure 4
Figure 4
IGF‐1 deficiency impairs mediation of CBF responses by eicosanoid gliotransmitters: role in neurovascular uncoupling. (A) Indomethacin‐sensitive, prostaglandin‐mediated portion of the CBF response (calculated based on the percentage decline in CBF in the presence of INDO) measured above the barrel field of the primary somatosensory cortex in response to whisker stimulation in control and IGF‐1‐deficient (Igf1 f/f + TBG‐Cre‐AAV8) mice (n = 6 in each group, *P < 0.05 vs. control; # P < 0.05 vs. control w/o INDO; & P < 0.05 vs. Igf1 f/f + TBG‐Cre‐AAV8 w/o INDO). (B) MS‐PPOH‐sensitive, EET‐mediated portion of the CBF response (calculated based on the percentage decline in CBF in the presence of MS‐PPOH) measured above the barrel field of the primary somatosensory cortex in response to whisker stimulation in control and IGF‐1‐deficient (Igf1 f/f + TBG‐Cre‐AAV8) mice (n = 6 in each group, *P < 0.05 vs. control; # P < 0.05 vs. control w/o MS‐PPOH; & P < 0.05 vs. Igf1 f/f + TBG‐Cre‐AAV8 w/o MS‐PPOH). (C) HET0016‐sensitive, 20‐HETE‐mediated portion of the CBF response (calculated based on the percentage decline in CBF in the presence of the cytochrome P450 ω‐hydroxylase inhibitor HET0016) measured above the barrel field of the primary somatosensory cortex in response to whisker stimulation in control and IGF‐1‐deficient (Igf1 f/f + TBG‐Cre‐AAV8) mice (n = 6 in each group, *P < 0.05 vs. control; # P < 0.05 vs. control w/o HET0016; & P < 0.05 vs. Igf1 f/f + TBG‐Cre‐AAV8 w/o HET0016). (D–E) Production of 14,15 EET (D) and 20‐HETE (E) in glutamate‐activated brain slices from control and Igf1 f/f + TBG‐Cre‐AAV8 mice as measured by liquid chromatography/mass spectrometry (LC/MS) (n = 6 in each group; *P < 0.05 vs. control; see Methods). (F) qPCR data showing mRNA expression of cyclooxygenase‐1 and cyclooxygenase‐2 (Ptgs1, Ptgs2) and EET‐producing epoxygenases (Cyp2j6, Cyp2c55) in isolated astrocytes, and 20‐HETE‐producing ω‐hydroxylases (Cyp4a10, Cyp4a12, Cyp4a14) in cortical samples of control and IGF‐1‐deficient mice (n = 5 in each group). *P < 0.05 vs. control. Data are mean ± S.E.M. (G) Proposed mechanisms by which age‐related IGF‐1 deficiency may impair neurovascular coupling responses (see Discussion). The model predicts that IGF‐1 deficiency both alters astrocytic production of eicosanoid gliotransmitters and impairs cerebromicrovascular endothelial function.
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