Background: Progressive supranuclear palsy (PSP) is a rare movement disorder; abnormally phosphor... more Background: Progressive supranuclear palsy (PSP) is a rare movement disorder; abnormally phosphorylated tau is the primary pathological lesion. A genome-wide association study (GWAS) identified 3 significant PSP risk loci in addition to the established H1 risk haplotype at the MAPT locus. We and others have shown that some of the SNPs implicated by PSP GWAS also associate with altered expression of proximal genes (in-cis) implicating transcriptional alterations as a possible disease mechanism. Gene expression can be influenced by both genetic and epigenetic factors; identifying and understanding the role of transcriptional control in the brains of PSP subjects may identify novel genes and indicate mechanism of action for future therapeutic targeting. We have previously collected gene expression profiles from 107 temporal cortex and 98 cerebellum PSP samples using the IlluminaWhole-Genome DASL assay (WG-DASL) and 85 overlapping temporal cortex samples using RNAseq. DNA methylation (RRBS) was also investigated in 46 of the same temporal cortex samples. We are pursuing findings from these previous studies in an additional cohort of 192 temporal cortex PSP samples. Methods: RNA was isolated from brain tissue using the Ambion RNAqueous kit. Gene expression was studied in 192 temporal cortex PSP samples using WGDASL; all gene expression measures underwent appropriate data QC. All samples have existing GWAS genotypes (Hoglinger et al, 2011). eQTL analysis was implemented in PLINK using linear regression, additive model, including appropriate covariates. Results: One sample failed quality control. In the remaining 191 PSP samples, 25,809 of the 29,377 probes (18,516 genes) showed signal above background levels (detection p<0.05) in greater than 50% of the subjects. eQTL analysis of SNPs previously implicated by PSP GWAS and our eQTL studies (Zou et al, 2012) replicated our previous findings in the same direction as we had previously reported: rs11568653-SLCO1A2: beta1⁄4 -0.89, p1⁄4 6.32E-13 and rs1768208 MOBP: beta1⁄4 0.37, p1⁄4 2.85E-03. Genome-wide eQTLanalysis is currently underway.Conclusions:Herewe confirmed association of the PSP protective alleles for two PSP GWAS SNPs with decreased SLCO1A2 and increased MOBP levels. Genomewide eQTL analysis may reveal additional PSP candidate genes.
American Journal of Physiology-Renal Physiology, 2021
We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the fawn... more We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the fawn-hooded hypertensive (FHH) rat is caused, at least in part, by a mutation in γ-adducin (ADD3) that attenuates renal vascular function. The present study explored whether Add3 contributes to the modulation of podocyte structure and function using FHH and FHH. Add3 transgenic rats. The expression of ADD3 on the membrane of primary podocytes isolated from FHH was reduced compared with FHH. Add3 transgenic rats. We found that F-actin nets, which are typically localized in the lamellipodia, replaced unbranched stress fibers in conditionally immortalized mouse podocytes transfected with Add3 Dicer-substrate short interfering RNA (DsiRNA) and primary podocytes isolated from FHH rats. There were increased F/G-actin ratios and expression of the Arp2/3 complexes throughout FHH podocytes in association with reduced synaptopodin and RhoA but enhanced Rac1 and CDC42 expression in the renal cortex, gl...
ABSTRACTWe previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response... more ABSTRACTWe previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, N-Hydroxy-N′-(4-butyl-2-methylphenyl)-formamidine (HET0016) but restored with 20-HETE analog 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (WIT003). Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and rescued by WIT003. Lastly, HET0016 impaired well autoregulated CBF in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in CBF autoregulation.
Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental is... more Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental ischemia and chronic inflammation that includes increased CD4+ T cells, B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1AA), and activation of the complement system. Previous studies have shown AT1-AA is produced in patients with COVID-19 infection. Interestingly, having had COVID-19 during pregnancy is associated with increased incidence of developing a PE phenotype during pregnancy. We have previously shown an important role for B cell depletion or AT1AA inhibition to attenuate HTN in rat models of PE. Collectively, this data suggests B cells contribute to PE development and that B cells may increase incidence of PE in patients with a history (Hx) of COVID-19 during pregnancy through production of the AT1AA. We hypothesize B cells from PE or CV Hx PE patients produce AT1AA resulting in HTN and complement activation in pregnancy. Placental B cells were isolated from normal pregnant (NP), PE, normotensive (NT) CV Hx, or PE CV Hx patients at delivery. B cells were transferred i.p. into pregnant athymic rats at gestation (GD) 12. On GD18, carotid catheters were inserted. On GD19, blood pressure was measured and tissues collected. PE B cell recipients had increased Mean Arterial Pressure (MAP) (115±3 mmHg n=6) compared to NP B cell recipients (97±4 mmHg n=6 p&lt;0.05). PE B cell recipients had increased AT1AA (20±2 ΔBPM n=4) compared to NP B cell recipients (6±1 ΔBPM n=4 p&lt;0.05). PE B cell recipients had increased markers of complement activation such as reduced plasma C4 (1302±169 μg/mL n=4) and C3 (516±45 μg/mL n=4) compared to recipients of NP B cells (2348±338 μg/mL n=4 p&lt;0.05) and (790±66 μg/mL n=4 p&lt;0.05) respectively. CV Hx PE B cell recipients had elevated MAP (108±3 mmHg n=4) compared to CV Hx NT B cell recipients (101±7 mmHg n=4) and increased AT1AA (24±3 ΔBPM n=3) compared to CV Hx NT B cell Recipients (4±1 ΔBPM n=4 p&lt;0.05). Collectively, this study demonstrates an important role for B cells to cause HTN during pregnancy; and indicates that B cells contribute to a higher incidence of PE in women with a Hx of CV infection during pregnancy possibly by secreting AT1-AA.
20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactiva... more 20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactivating mutations in the CYP enzymes that produce 20-HETE are associated with hypertension and stroke in man. We previously revealed that inactivating variants of CYP4A/F enzymes are associated with dementia in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NS) population. 20-HETE is involved with sodium regulation in the kidney and is a powerful vasoconstrictor. It was recently discovered that CCL5 and 20-HETE share the same receptor, GPR75. We previously found that 20-HETE constricts and augments the myogenic response (MR) of the middle cerebral artery (MCA) and renal afferent arteriole. However, whether CCL5 has any effect on penetrating arterioles (PAs) and interacts with 20-HETE is unknown. We found that GPR75 is expressed in PAs and pericytes in the brain. CYP4A is also expressed in pericytes and is inversely proportional to levels of GPR75 in the brain. In the present study, we found that 20-HETE contributes to the basal myogenic tone of PAs in SD rats. Administration of HET0016, a 20-HETE synthesis inhibitor, dilated the PA by 34 ± 3% (n = 6) under 10 mmHg perfusion pressure. Administration of WIT003, a 20-HETE agonist, constricted the vessel by 23 ± 4% (n = 6) under the same perfusion pressure. We found that CCL5 also reduced PA diameter by 20 ± 4% (n = 7) in SD rats under 10 mmHg perfusion pressure. Moreover, we compared the response to CCL5 in SS rats that are 20-HETE deficient and SS.CYP4A1 transgenic rats in which 20-HETE production is restored. PAs isolated from SS rats treated with 0.1 nM CCL5 constricted by 9 ± 5% (n = 6) while those treated with 10 nM constricted by 12 ± 3% (n = 6). CCL5 had a greater response in PAs from the SS.CYP4A1 strain, and the diameter of the PAs constricted by 14 ± 2% (n = 5) and 24 ± 5% (n = 5) in response to 0.1 and 10 nM CCL5, respectively. These results demonstrate that CCL5 has a direct effect on PAs similar to 20-HETE that acts via the GPR75 receptor. However, further study is needed to determine how CCL5 and 20-HETE interact to promote vasoconstriction. These studies would help further understand the involvement of 20-HETE in disease and potentially identify novel drug targets.
Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental is... more Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental ischemia and chronic inflammation that includes increased CD4+ T cells, B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1AA), and activation of the complement system. Previous studies have shown AT1-AA is produced in patients with COVID-19 infection. Interestingly, having had COVID-19 during pregnancy is associated with increased incidence of developing a PE phenotype during pregnancy. We have previously shown an important role for B cell depletion or AT1AA inhibition to attenuate HTN in rat models of PE. Collectively, this data suggests B cells contribute to PE development and that B cells may increase incidence of PE in patients with a history (Hx) of COVID-19 during pregnancy through production of the AT1AA. We hypothesize B cells from PE or CV Hx PE patients produce AT1AA resulting in HTN and complement activation in pregnancy. Placental B cells...
We have previously identified an inactivating mutation of ADD3 in FHH rats which is associated wi... more We have previously identified an inactivating mutation of ADD3 in FHH rats which is associated with impaired myogenic reactivity of renal arterioles and podocyte function, and contributes to the development of CKD. We have found that SNPs in human ADD1 or ADD3 in the same region as Add3 in FHH rats are linked to reductions in brain volumes and impaired performance on cognitive tests in 4,286 elderly patients (67-90 years old) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), but the mechanisms of these pathologies are unclear. The present study examined cerebral hemodynamics and cognitive function in FHH versus FHH.1BN and FHH. Add3 rats that express the WT Add3 gene. The myogenic responses of the middle cerebral artery (MCA) and parenchymal arterioles (PA) were impaired in FHH rats. MCA diameter decreased by 15-20% in FHH.1BN (n = 27) and FHH. Add3 (n = 10) transgenic rats, but increased by 9 ± 3% in FHH rats (n = 15) when perfusion pressure was increased ...
American Journal of Physiology-Heart and Circulatory Physiology, 2021
This study demonstrates that the loss of contractile capability in pericytes in diabetes is assoc... more This study demonstrates that the loss of contractile capability in pericytes in diabetes is associated with enhanced ROS and reduced ATP production. Enhanced advanced glycation end products (AGEs) in diabetes accompany with reduced pericyte and endothelial tight junction coverage in the cortical capillaries of old diabetic rats. These results suggest our previous findings that the impaired cerebral hemodynamics, BBB leakage, and cognitive impairments in old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction.
We recently reported that cerebral vascular dysfunction leads to impaired autoregulation of cereb... more We recently reported that cerebral vascular dysfunction leads to impaired autoregulation of cerebral blood flow (CBF), neurovascular coupling (NVC), and blood-brain barrier (BBB) leakage. The present study examined if cerebral vascular dysfunction precedes cognitive impairment in the TgF344-AD (AD) rat model of Alzheimer's disease. In the present study, we confirmed that the AD rats develop learning and memory deficits beginning at 24-week of age using an eight-arm water maze. AD rats (n = 11) took a longer time to escape and displayed more errors than age-matched wildtype (WT) rats (n = 6). We also completed a longitudinal comparison of the myogenic response (MR) of the middle cerebral artery (MCA) and found that the MR was similar in AD and WT rats at 8- to 12-week of age when perfusion pressure was increased from 40 to 180 mmHg. However, the MR was significantly reduced in 16-week old AD rats (n = 6) as the inner diameter of the MCA only decreased by 8.2 ± 2.4% when perfusion...
We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and aut... more We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, HET0016 but restored with 20-HETE analog WIT003. Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and were rescued by WIT003. The myogenic response of the PA was abolished in SS and was restored in SS.BN5 and SS.Cyp4a1 rats. HET0016 enhanced CBF and impaired its autoregulation in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in controlling cerebral vascular function.
Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Desp... more Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca2+ influx through TRPC6 activates the cAMP (adenosine 3’,5’-cyclic monophosphate) response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of N-methyl-d-aspartate (NMDA) receptors of neurons by posttranslational...
Background: Progressive supranuclear palsy (PSP) is a rare movement disorder; abnormally phosphor... more Background: Progressive supranuclear palsy (PSP) is a rare movement disorder; abnormally phosphorylated tau is the primary pathological lesion. A genome-wide association study (GWAS) identified 3 significant PSP risk loci in addition to the established H1 risk haplotype at the MAPT locus. We and others have shown that some of the SNPs implicated by PSP GWAS also associate with altered expression of proximal genes (in-cis) implicating transcriptional alterations as a possible disease mechanism. Gene expression can be influenced by both genetic and epigenetic factors; identifying and understanding the role of transcriptional control in the brains of PSP subjects may identify novel genes and indicate mechanism of action for future therapeutic targeting. We have previously collected gene expression profiles from 107 temporal cortex and 98 cerebellum PSP samples using the IlluminaWhole-Genome DASL assay (WG-DASL) and 85 overlapping temporal cortex samples using RNAseq. DNA methylation (RRBS) was also investigated in 46 of the same temporal cortex samples. We are pursuing findings from these previous studies in an additional cohort of 192 temporal cortex PSP samples. Methods: RNA was isolated from brain tissue using the Ambion RNAqueous kit. Gene expression was studied in 192 temporal cortex PSP samples using WGDASL; all gene expression measures underwent appropriate data QC. All samples have existing GWAS genotypes (Hoglinger et al, 2011). eQTL analysis was implemented in PLINK using linear regression, additive model, including appropriate covariates. Results: One sample failed quality control. In the remaining 191 PSP samples, 25,809 of the 29,377 probes (18,516 genes) showed signal above background levels (detection p<0.05) in greater than 50% of the subjects. eQTL analysis of SNPs previously implicated by PSP GWAS and our eQTL studies (Zou et al, 2012) replicated our previous findings in the same direction as we had previously reported: rs11568653-SLCO1A2: beta1⁄4 -0.89, p1⁄4 6.32E-13 and rs1768208 MOBP: beta1⁄4 0.37, p1⁄4 2.85E-03. Genome-wide eQTLanalysis is currently underway.Conclusions:Herewe confirmed association of the PSP protective alleles for two PSP GWAS SNPs with decreased SLCO1A2 and increased MOBP levels. Genomewide eQTL analysis may reveal additional PSP candidate genes.
American Journal of Physiology-Renal Physiology, 2021
We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the fawn... more We recently reported that the enhanced susceptibility to chronic kidney disease (CKD) in the fawn-hooded hypertensive (FHH) rat is caused, at least in part, by a mutation in γ-adducin (ADD3) that attenuates renal vascular function. The present study explored whether Add3 contributes to the modulation of podocyte structure and function using FHH and FHH. Add3 transgenic rats. The expression of ADD3 on the membrane of primary podocytes isolated from FHH was reduced compared with FHH. Add3 transgenic rats. We found that F-actin nets, which are typically localized in the lamellipodia, replaced unbranched stress fibers in conditionally immortalized mouse podocytes transfected with Add3 Dicer-substrate short interfering RNA (DsiRNA) and primary podocytes isolated from FHH rats. There were increased F/G-actin ratios and expression of the Arp2/3 complexes throughout FHH podocytes in association with reduced synaptopodin and RhoA but enhanced Rac1 and CDC42 expression in the renal cortex, gl...
ABSTRACTWe previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response... more ABSTRACTWe previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, N-Hydroxy-N′-(4-butyl-2-methylphenyl)-formamidine (HET0016) but restored with 20-HETE analog 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (WIT003). Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and rescued by WIT003. Lastly, HET0016 impaired well autoregulated CBF in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in CBF autoregulation.
Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental is... more Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental ischemia and chronic inflammation that includes increased CD4+ T cells, B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1AA), and activation of the complement system. Previous studies have shown AT1-AA is produced in patients with COVID-19 infection. Interestingly, having had COVID-19 during pregnancy is associated with increased incidence of developing a PE phenotype during pregnancy. We have previously shown an important role for B cell depletion or AT1AA inhibition to attenuate HTN in rat models of PE. Collectively, this data suggests B cells contribute to PE development and that B cells may increase incidence of PE in patients with a history (Hx) of COVID-19 during pregnancy through production of the AT1AA. We hypothesize B cells from PE or CV Hx PE patients produce AT1AA resulting in HTN and complement activation in pregnancy. Placental B cells were isolated from normal pregnant (NP), PE, normotensive (NT) CV Hx, or PE CV Hx patients at delivery. B cells were transferred i.p. into pregnant athymic rats at gestation (GD) 12. On GD18, carotid catheters were inserted. On GD19, blood pressure was measured and tissues collected. PE B cell recipients had increased Mean Arterial Pressure (MAP) (115±3 mmHg n=6) compared to NP B cell recipients (97±4 mmHg n=6 p&lt;0.05). PE B cell recipients had increased AT1AA (20±2 ΔBPM n=4) compared to NP B cell recipients (6±1 ΔBPM n=4 p&lt;0.05). PE B cell recipients had increased markers of complement activation such as reduced plasma C4 (1302±169 μg/mL n=4) and C3 (516±45 μg/mL n=4) compared to recipients of NP B cells (2348±338 μg/mL n=4 p&lt;0.05) and (790±66 μg/mL n=4 p&lt;0.05) respectively. CV Hx PE B cell recipients had elevated MAP (108±3 mmHg n=4) compared to CV Hx NT B cell recipients (101±7 mmHg n=4) and increased AT1AA (24±3 ΔBPM n=3) compared to CV Hx NT B cell Recipients (4±1 ΔBPM n=4 p&lt;0.05). Collectively, this study demonstrates an important role for B cells to cause HTN during pregnancy; and indicates that B cells contribute to a higher incidence of PE in women with a Hx of CV infection during pregnancy possibly by secreting AT1-AA.
20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactiva... more 20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactivating mutations in the CYP enzymes that produce 20-HETE are associated with hypertension and stroke in man. We previously revealed that inactivating variants of CYP4A/F enzymes are associated with dementia in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NS) population. 20-HETE is involved with sodium regulation in the kidney and is a powerful vasoconstrictor. It was recently discovered that CCL5 and 20-HETE share the same receptor, GPR75. We previously found that 20-HETE constricts and augments the myogenic response (MR) of the middle cerebral artery (MCA) and renal afferent arteriole. However, whether CCL5 has any effect on penetrating arterioles (PAs) and interacts with 20-HETE is unknown. We found that GPR75 is expressed in PAs and pericytes in the brain. CYP4A is also expressed in pericytes and is inversely proportional to levels of GPR75 in the brain. In the present study, we found that 20-HETE contributes to the basal myogenic tone of PAs in SD rats. Administration of HET0016, a 20-HETE synthesis inhibitor, dilated the PA by 34 ± 3% (n = 6) under 10 mmHg perfusion pressure. Administration of WIT003, a 20-HETE agonist, constricted the vessel by 23 ± 4% (n = 6) under the same perfusion pressure. We found that CCL5 also reduced PA diameter by 20 ± 4% (n = 7) in SD rats under 10 mmHg perfusion pressure. Moreover, we compared the response to CCL5 in SS rats that are 20-HETE deficient and SS.CYP4A1 transgenic rats in which 20-HETE production is restored. PAs isolated from SS rats treated with 0.1 nM CCL5 constricted by 9 ± 5% (n = 6) while those treated with 10 nM constricted by 12 ± 3% (n = 6). CCL5 had a greater response in PAs from the SS.CYP4A1 strain, and the diameter of the PAs constricted by 14 ± 2% (n = 5) and 24 ± 5% (n = 5) in response to 0.1 and 10 nM CCL5, respectively. These results demonstrate that CCL5 has a direct effect on PAs similar to 20-HETE that acts via the GPR75 receptor. However, further study is needed to determine how CCL5 and 20-HETE interact to promote vasoconstriction. These studies would help further understand the involvement of 20-HETE in disease and potentially identify novel drug targets.
Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental is... more Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental ischemia and chronic inflammation that includes increased CD4+ T cells, B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1AA), and activation of the complement system. Previous studies have shown AT1-AA is produced in patients with COVID-19 infection. Interestingly, having had COVID-19 during pregnancy is associated with increased incidence of developing a PE phenotype during pregnancy. We have previously shown an important role for B cell depletion or AT1AA inhibition to attenuate HTN in rat models of PE. Collectively, this data suggests B cells contribute to PE development and that B cells may increase incidence of PE in patients with a history (Hx) of COVID-19 during pregnancy through production of the AT1AA. We hypothesize B cells from PE or CV Hx PE patients produce AT1AA resulting in HTN and complement activation in pregnancy. Placental B cells...
We have previously identified an inactivating mutation of ADD3 in FHH rats which is associated wi... more We have previously identified an inactivating mutation of ADD3 in FHH rats which is associated with impaired myogenic reactivity of renal arterioles and podocyte function, and contributes to the development of CKD. We have found that SNPs in human ADD1 or ADD3 in the same region as Add3 in FHH rats are linked to reductions in brain volumes and impaired performance on cognitive tests in 4,286 elderly patients (67-90 years old) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), but the mechanisms of these pathologies are unclear. The present study examined cerebral hemodynamics and cognitive function in FHH versus FHH.1BN and FHH. Add3 rats that express the WT Add3 gene. The myogenic responses of the middle cerebral artery (MCA) and parenchymal arterioles (PA) were impaired in FHH rats. MCA diameter decreased by 15-20% in FHH.1BN (n = 27) and FHH. Add3 (n = 10) transgenic rats, but increased by 9 ± 3% in FHH rats (n = 15) when perfusion pressure was increased ...
American Journal of Physiology-Heart and Circulatory Physiology, 2021
This study demonstrates that the loss of contractile capability in pericytes in diabetes is assoc... more This study demonstrates that the loss of contractile capability in pericytes in diabetes is associated with enhanced ROS and reduced ATP production. Enhanced advanced glycation end products (AGEs) in diabetes accompany with reduced pericyte and endothelial tight junction coverage in the cortical capillaries of old diabetic rats. These results suggest our previous findings that the impaired cerebral hemodynamics, BBB leakage, and cognitive impairments in old DM model are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction.
We recently reported that cerebral vascular dysfunction leads to impaired autoregulation of cereb... more We recently reported that cerebral vascular dysfunction leads to impaired autoregulation of cerebral blood flow (CBF), neurovascular coupling (NVC), and blood-brain barrier (BBB) leakage. The present study examined if cerebral vascular dysfunction precedes cognitive impairment in the TgF344-AD (AD) rat model of Alzheimer's disease. In the present study, we confirmed that the AD rats develop learning and memory deficits beginning at 24-week of age using an eight-arm water maze. AD rats (n = 11) took a longer time to escape and displayed more errors than age-matched wildtype (WT) rats (n = 6). We also completed a longitudinal comparison of the myogenic response (MR) of the middle cerebral artery (MCA) and found that the MR was similar in AD and WT rats at 8- to 12-week of age when perfusion pressure was increased from 40 to 180 mmHg. However, the MR was significantly reduced in 16-week old AD rats (n = 6) as the inner diameter of the MCA only decreased by 8.2 ± 2.4% when perfusion...
We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and aut... more We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, HET0016 but restored with 20-HETE analog WIT003. Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and were rescued by WIT003. The myogenic response of the PA was abolished in SS and was restored in SS.BN5 and SS.Cyp4a1 rats. HET0016 enhanced CBF and impaired its autoregulation in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in controlling cerebral vascular function.
Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Desp... more Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca2+ influx through TRPC6 activates the cAMP (adenosine 3’,5’-cyclic monophosphate) response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of N-methyl-d-aspartate (NMDA) receptors of neurons by posttranslational...
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Papers by Baoying Zheng