Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice
In sickle cell disease, intravascular sickling and attendant flow abnormalities underlie the chronic inflammation and vascular endothelial abnormalities. However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events a...
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| creator | Kaul, Dhananjay K Liu, Xiao-du Chang, Hee-Yoon Nagel, Ronald L Fabry, Mary E |
| description | In sickle cell disease, intravascular sickling and attendant flow abnormalities underlie the chronic inflammation and vascular endothelial abnormalities. However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative stress will affect microvascular regulatory mechanisms. In the present studies, we have examined whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice (which express exclusively human alpha- and beta(S)-globins with |
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However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative stress will affect microvascular regulatory mechanisms. In the present studies, we have examined whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice (which express exclusively human alpha- and beta(S)-globins with <1% gamma-globin levels) are amenable to correction with increased levels of antisickling fetal hemoglobin (HbF). In BERK mice, sickling, increased oxidative stress, and hemolytic anemia are accompanied by vasodilation, compensatory increases in eNOS and COX-2, and attenuated vascular responses to NO-mediated vasoactive stimuli and norepinephrine. The hypotension and vasodilation (required for adequate oxygen delivery in the face of chronic anemia) are mediated by non-NO vasodilators (i.e., prostacyclin) as evidenced by induction of COX-2. In BERK mice, the resistance to NO-mediated vasodilators is associated with increased oxidative stress and hemolytic rate, and in BERK + gamma mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced oxidative stress and hemolytic rate. Furthermore, BERK + gamma mice show normalization of vessel diameters, and eNOS and COX-2 expression. These results demonstrate a strong relationship between sickling and microvascular function in sickle cell disease.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI200421633</identifier><identifier>PMID: 15489961</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Acetylcholine - pharmacology ; Anemia ; Anemia, Sickle Cell - genetics ; Anemia, Sickle Cell - metabolism ; Animals ; Bioavailability ; Biomedical research ; Blood ; Cell Adhesion - physiology ; Cyclooxygenase 2 ; Endothelium ; Endothelium, Vascular - cytology ; Endothelium, Vascular - drug effects ; Endothelium, Vascular - metabolism ; Enzyme Inhibitors - pharmacology ; Female ; Fetal Hemoglobin - metabolism ; Hematology ; Hemodynamics ; Hemoglobin ; Hemoglobin, Sickle - genetics ; Hemoglobin, Sickle - metabolism ; Hemolysis - physiology ; Humans ; Inflammation ; Isoenzymes - metabolism ; Male ; Membrane Proteins ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Microcirculation - metabolism ; Muscle, Skeletal - cytology ; Muscle, Skeletal - metabolism ; NG-Nitroarginine Methyl Ester - pharmacology ; Nitric Oxide - metabolism ; Nitric Oxide Synthase - metabolism ; Nitric Oxide Synthase Type II ; Nitric Oxide Synthase Type III ; Nitroprusside - pharmacology ; Oxidative Stress ; Prostaglandin-Endoperoxide Synthases - metabolism ; Regulation ; Sickle cell disease ; Tyrosine - analogs & derivatives ; Tyrosine - metabolism ; Vasodilation - physiology ; Vasodilator Agents - pharmacology</subject><ispartof>The Journal of clinical investigation, 2004-10, Vol.114 (8), p.1136-1145</ispartof><rights>Copyright American Society for Clinical Investigation Oct 2004</rights><rights>2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-d9fd8709129c31f3192a6f65ba2eb03298565af5dee0fee6bad1097cc92b43073</citedby><cites>FETCH-LOGICAL-c406t-d9fd8709129c31f3192a6f65ba2eb03298565af5dee0fee6bad1097cc92b43073</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC522244/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC522244/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15489961$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaul, Dhananjay K</creatorcontrib><creatorcontrib>Liu, Xiao-du</creatorcontrib><creatorcontrib>Chang, Hee-Yoon</creatorcontrib><creatorcontrib>Nagel, Ronald L</creatorcontrib><creatorcontrib>Fabry, Mary E</creatorcontrib><title>Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>In sickle cell disease, intravascular sickling and attendant flow abnormalities underlie the chronic inflammation and vascular endothelial abnormalities. However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative stress will affect microvascular regulatory mechanisms. In the present studies, we have examined whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice (which express exclusively human alpha- and beta(S)-globins with <1% gamma-globin levels) are amenable to correction with increased levels of antisickling fetal hemoglobin (HbF). In BERK mice, sickling, increased oxidative stress, and hemolytic anemia are accompanied by vasodilation, compensatory increases in eNOS and COX-2, and attenuated vascular responses to NO-mediated vasoactive stimuli and norepinephrine. The hypotension and vasodilation (required for adequate oxygen delivery in the face of chronic anemia) are mediated by non-NO vasodilators (i.e., prostacyclin) as evidenced by induction of COX-2. In BERK mice, the resistance to NO-mediated vasodilators is associated with increased oxidative stress and hemolytic rate, and in BERK + gamma mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced oxidative stress and hemolytic rate. Furthermore, BERK + gamma mice show normalization of vessel diameters, and eNOS and COX-2 expression. These results demonstrate a strong relationship between sickling and microvascular function in sickle cell disease.</description><subject>Acetylcholine - pharmacology</subject><subject>Anemia</subject><subject>Anemia, Sickle Cell - genetics</subject><subject>Anemia, Sickle Cell - metabolism</subject><subject>Animals</subject><subject>Bioavailability</subject><subject>Biomedical research</subject><subject>Blood</subject><subject>Cell Adhesion - physiology</subject><subject>Cyclooxygenase 2</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - cytology</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Fetal Hemoglobin - metabolism</subject><subject>Hematology</subject><subject>Hemodynamics</subject><subject>Hemoglobin</subject><subject>Hemoglobin, Sickle - genetics</subject><subject>Hemoglobin, Sickle - metabolism</subject><subject>Hemolysis - physiology</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Isoenzymes - metabolism</subject><subject>Male</subject><subject>Membrane Proteins</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Microcirculation - metabolism</subject><subject>Muscle, Skeletal - cytology</subject><subject>Muscle, Skeletal - metabolism</subject><subject>NG-Nitroarginine Methyl Ester - pharmacology</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Nitric Oxide Synthase Type II</subject><subject>Nitric Oxide Synthase Type III</subject><subject>Nitroprusside - pharmacology</subject><subject>Oxidative Stress</subject><subject>Prostaglandin-Endoperoxide Synthases - metabolism</subject><subject>Regulation</subject><subject>Sickle cell disease</subject><subject>Tyrosine - analogs & derivatives</subject><subject>Tyrosine - metabolism</subject><subject>Vasodilation - physiology</subject><subject>Vasodilator Agents - pharmacology</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkb1PHDEQxS0UBAdJlzpapUjFgr93XaRAJz51Eg0UqSyvd3yY27WJvYuU_z5GdwqEaor3e6M38xD6SvApIQ09u13eUIw5JZKxPbQgQrR1S1n7CS0wpqRWDWsP0VHOTxgTzgU_QIdE8FYpSRbo14VzYKcqusrBZIbqEca4HmLnQxVDNXqb4ovJdh5MqhKsy5x8EYqcvd0MUE3JhLyG4G29CdFu4jy92uAz2ndmyPBlN4_Rw-XF_fK6Xt1d3SzPV7XlWE51r1zfNlgRqiwjjhFFjXRSdIZChxlVrZDCONEDYAcgO9MTrBprFe04ww07Rj-3e5_nboTeQiiJBv2c_GjSHx2N1_8rwT_qdXzRglLKefH_2PlT_D1DnvTos4VhMAHinLWUqlGNkAX8_gF8inMK5TZdChBCNgIX6GQLlb_lnMD9C0Kwfu1Lv--r4N_eh3-DdwWxv_S0kgs</recordid><startdate>20041001</startdate><enddate>20041001</enddate><creator>Kaul, Dhananjay K</creator><creator>Liu, Xiao-du</creator><creator>Chang, Hee-Yoon</creator><creator>Nagel, Ronald L</creator><creator>Fabry, Mary E</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20041001</creationdate><title>Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice</title><author>Kaul, Dhananjay K ; Liu, Xiao-du ; Chang, Hee-Yoon ; Nagel, Ronald L ; Fabry, Mary E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-d9fd8709129c31f3192a6f65ba2eb03298565af5dee0fee6bad1097cc92b43073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Acetylcholine - pharmacology</topic><topic>Anemia</topic><topic>Anemia, Sickle Cell - genetics</topic><topic>Anemia, Sickle Cell - metabolism</topic><topic>Animals</topic><topic>Bioavailability</topic><topic>Biomedical research</topic><topic>Blood</topic><topic>Cell Adhesion - physiology</topic><topic>Cyclooxygenase 2</topic><topic>Endothelium</topic><topic>Endothelium, Vascular - cytology</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Fetal Hemoglobin - metabolism</topic><topic>Hematology</topic><topic>Hemodynamics</topic><topic>Hemoglobin</topic><topic>Hemoglobin, Sickle - genetics</topic><topic>Hemoglobin, Sickle - metabolism</topic><topic>Hemolysis - physiology</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Isoenzymes - metabolism</topic><topic>Male</topic><topic>Membrane Proteins</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Microcirculation - metabolism</topic><topic>Muscle, Skeletal - cytology</topic><topic>Muscle, Skeletal - metabolism</topic><topic>NG-Nitroarginine Methyl Ester - pharmacology</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Synthase - metabolism</topic><topic>Nitric Oxide Synthase Type II</topic><topic>Nitric Oxide Synthase Type III</topic><topic>Nitroprusside - pharmacology</topic><topic>Oxidative Stress</topic><topic>Prostaglandin-Endoperoxide Synthases - metabolism</topic><topic>Regulation</topic><topic>Sickle cell disease</topic><topic>Tyrosine - analogs & derivatives</topic><topic>Tyrosine - metabolism</topic><topic>Vasodilation - physiology</topic><topic>Vasodilator Agents - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaul, Dhananjay K</creatorcontrib><creatorcontrib>Liu, Xiao-du</creatorcontrib><creatorcontrib>Chang, Hee-Yoon</creatorcontrib><creatorcontrib>Nagel, Ronald L</creatorcontrib><creatorcontrib>Fabry, Mary E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaul, Dhananjay K</au><au>Liu, Xiao-du</au><au>Chang, Hee-Yoon</au><au>Nagel, Ronald L</au><au>Fabry, Mary E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2004-10-01</date><risdate>2004</risdate><volume>114</volume><issue>8</issue><spage>1136</spage><epage>1145</epage><pages>1136-1145</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>In sickle cell disease, intravascular sickling and attendant flow abnormalities underlie the chronic inflammation and vascular endothelial abnormalities. However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative stress will affect microvascular regulatory mechanisms. In the present studies, we have examined whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice (which express exclusively human alpha- and beta(S)-globins with <1% gamma-globin levels) are amenable to correction with increased levels of antisickling fetal hemoglobin (HbF). In BERK mice, sickling, increased oxidative stress, and hemolytic anemia are accompanied by vasodilation, compensatory increases in eNOS and COX-2, and attenuated vascular responses to NO-mediated vasoactive stimuli and norepinephrine. The hypotension and vasodilation (required for adequate oxygen delivery in the face of chronic anemia) are mediated by non-NO vasodilators (i.e., prostacyclin) as evidenced by induction of COX-2. In BERK mice, the resistance to NO-mediated vasodilators is associated with increased oxidative stress and hemolytic rate, and in BERK + gamma mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced oxidative stress and hemolytic rate. Furthermore, BERK + gamma mice show normalization of vessel diameters, and eNOS and COX-2 expression. These results demonstrate a strong relationship between sickling and microvascular function in sickle cell disease.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>15489961</pmid><doi>10.1172/JCI200421633</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acetylcholine - pharmacology Anemia Anemia, Sickle Cell - genetics Anemia, Sickle Cell - metabolism Animals Bioavailability Biomedical research Blood Cell Adhesion - physiology Cyclooxygenase 2 Endothelium Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Enzyme Inhibitors - pharmacology Female Fetal Hemoglobin - metabolism Hematology Hemodynamics Hemoglobin Hemoglobin, Sickle - genetics Hemoglobin, Sickle - metabolism Hemolysis - physiology Humans Inflammation Isoenzymes - metabolism Male Membrane Proteins Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microcirculation - metabolism Muscle, Skeletal - cytology Muscle, Skeletal - metabolism NG-Nitroarginine Methyl Ester - pharmacology Nitric Oxide - metabolism Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Nitroprusside - pharmacology Oxidative Stress Prostaglandin-Endoperoxide Synthases - metabolism Regulation Sickle cell disease Tyrosine - analogs & derivatives Tyrosine - metabolism Vasodilation - physiology Vasodilator Agents - pharmacology |
| title | Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice |
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