we used 2 g of total rna from human umbilical vein ecs ( huvecs ) cultured under normoxic or hypoxic conditions for 24 h and subjected to rna - seq analysis ( n  = 3 ) . after extracting the total rna from the samples , the left rna was fragmented into short fragments , then the first strand complementary deoxyribonucleic acid was synthesized by random hexamer - primer using the left rna fragments as templates . buffer , nucleotide triphosphates containing deoxyribose , ribonuclease h , and deoxyribonucleic acid polymerase i were added to synthesize the second strand . the double - strand complementary deoxyribonucleic acid was purified using the qiaquick polymerase chain reaction extraction kit ( qiagen , venlo , the netherlands ) and washed with elution buffer for end repair and poly(a ) addition . finally , sequencing adaptors were ligated to the fragments , which were purified by agarose gel electrophoresis and enriched by polymerase chain reaction amplification . the library products were sequenced using the hiseq 2000 ( illumina , san diego , california ) . to identify hypoxia - sensitive endothelial lncrnas , huvecs were first subjected to  24 h of hypoxia . in preliminary experiments , we  found this time point optimal for identifying regulations of a vast majority of lncrnas ( data not shown ) . hypoxia - sensitive noncoding rna expression was detected via 2 approaches , microarray- and rna - seq - based techniques . we first focused on the microarray - derived noncoding rna dataset to search for lncrnas using the following criteria : minimal 4-fold deregulation and intergenic lncrna localization . by this approach , we identified linc00323 ( lnc - dscam-1 ) to be the strongest ( 8-fold ) up - regulated lincrna after hypoxia ( probe uc002yyv ) ( online table  1 ) . rna - seq data identified 773 ( 403 up , 370 down ) significantly deregulated lncrnas ( figure  1a , online table  2 ) . the analysis of rna - seq data for protein - coding genes of huvecs cultured under normoxic or hypoxic conditions showed 8,156 ( 4,032 up , 4,124 down ) significantly deregulated mrnas ( figure  1b , online table  2 ) . the log2-fold expression changes derived from the 2 different technologies were significantly correlated both for lncrnas ( pearson correlation coefficient  = 0.43 , p  < 2.2   10 ) and for  protein - coding genes ( pearson correlation coefficient  = 0.74 , p  < 2.2   10 ) ( online figure  1 ) . rna - seq also confirmed enhanced expression of linc00323 ( lnc - dscam-1 ) under hypoxia ( online table  2 ) . in addition , from the rna - seq data , we identified another hypoxia - sensitive lncrna , mir503hg ( lnc - plac1 - 1 ) , on the basis of the following criteria : 1 ) minimal 4-fold up - regulation ; 2 ) base mean > 1,000 ; and 3 ) intergenic annotation . on the basis of these stringent criteria , we identified lnc - mst1p9 - 2 and lnc - plac1 - 1 as high propriety candidates but omitted lnc - mst1p9 - 2 from further studies because of potential protein - coding properties . subsequent validation experiments confirmed the hypoxia - dependent up - regulation of the previous 2 array- or rna - seq - derived lincrnas , linc00323 and mir503hg ( figure  1c and online figure  1 for other linc00323 transcript isoforms ) . cell compartment specific rna analysis revealed hypoxia - dependent enhanced cytoplasmic linc00323 - 003 expression , whereas mir503hg was increased both in the nuclear and cytoplasmic compartments ( figure  1c ) . high purity of subcellular compartment preparations was proved by screening expression of the nuclear enriched lncrna xist ( online figure  1 ) . endothelial up - regulation of these 2 lncrnas by hypoxia was cell - type specific , as this was not seen in human cardiac fibroblasts or human aortic smooth muscle cells exposed to hypoxia ( online figure  1 ) . the 2 lncrnas were considerably expressed in ecs and vascularized organs , such as kidneys ( data not shown ) . we  next sought to identify potential functional relevance for the identified lncrna candidates in human ecs . linc00323 is encoded on chromosome 21 and has 3 transcript isoforms 21 , 22 according to the lncrna database lncipedia and the ensembl genome browser ( figure  2a ) . we focused on linc00323 transcript variant 3 , as a small interfering rna ( sirna ) approach had obvious effects on ec biology to reduce cell number in  vitro . next to proangiogenic hypoxic signaling , endothelial vegf treatment also increased linc00323 - 003 expression ( figure  2b ) . multiple in  vitro assays were performed to clarify the functional relevance of endothelial linc00323 - 003 expression . because linc00323 - 003 was detectable in nuclear and cytoplasmatic compartments , we used both antisense - mediated sirna ( targeting cytoplasmic lncrnas ) and gapmer ( targeting nuclear lncrnas ) approaches in huvecs . both approaches in a transgenic linc00323 - 003 overexpressing ec line documented potent lncrna silencing ( online figure  2 ) . fluorescein transfection in ecs led to an accumulation in the nucleus ( online figure  2 ) . titration experiments for the sirna chemistry showed detrimental effects on ec viability in a range of 1 to 100 nmol / l sirna , whereas application of 100 pmol / l of sirna exhibited no significant effect ( online figure  2 ) . further sirna experiments were thus performed with 1 nmol / l of sirna to reduce potential off - target effects . both sirna- and gapmer - mediated linc00323 - 003 silencing led to an inhibition of human ec proliferation ( figure  2c , online figure  2 ) , suggesting cytoplasmic and nuclear linc00323 - 003 expression to be critical for endothelial proliferation . in line , linc00323 - 003 silencing increased the ratio of binucleic to total cells and led to an increase in ec size , suggesting proliferation defects ( online figures  2 and 3 ) . accordingly , the cell - cycle inhibitors p21 and p27 were up - regulated , whereas cell - cycle progression - relevant cyclin - dependent kinases 1 and 2 were reduced upon endothelial linc00323 - 003 silencing ( figure  2d , online figure  3 ) . migration capacity was also strongly attenuated by linc00323 - 003 loss ( online figure  3 ) . angiogenic capacity tested by capillary tube formation assays was significantly deteriorated upon linc00323 - 003 silencing ( figure  2e ) . this was paralleled by a repression of  proangiogenic vegfb and induction of the angiogenesis inhibitor thrombospondin ( online figure  3 ) . loss of linc00323 - 003 additionally inhibited proliferation - important extracellular signal  regulated kinase phosphorylation , and both led to a repression of the key endothelial transcription factor gata2 and proangiogenic sirtuin i ( online figure  3 , figure  2f ) . indeed , part of the detrimental actions of  linc00323 - 003 were mediated through gata2 silencing , as genetic overexpression of a  functional gata2 construct attenuated the linc00323 - 003 actions on ecs ( online figure  3 ) . interestingly , linc00323 - 003 silencing reduced gata2 protein but not mrna levels ( figure  2 g ) , suggesting a post - translational mechanism . using starbase 23 , 24 , a bioinformatic - based identification system , we found potential protein candidates interacting with linc00323 - 003 that are also involved in mrna translation and identified the translation initiation  factor eif4a3 . indeed , we were able to immunoprecipitate eif4a3 in human ecs ( figure  2h ) . rna  immunoprecipitation experiments in a stable linc00323 - 003-overexpression ec line revealed significant enrichment of linc00323 - 003 with immunoprecipitated eif4a3 compared with controls ( figure  2i ) . in addition , gata2 mrna was found to be associated with eif4a3 ( figure  2j ) . this suggests a scaffold function of linc00323 - 003 to bind proteins , such as the translation initiation factor eif4a3 ( central illustration ) . linc00323 - 003 silencing also caused impaired proliferative capacity of human coronary artery ecs , suggesting a broad impact of this lncrna on various types of ecs ( online figure  3 ) . the rna - seq - derived lincrna mir503hg is located at chromosome x , harbors a coding sequence of mir-503 , and is adjacent to mir-424 ( figure  3a ) . indeed , analysis of primary mir-503 and mature mir-503 expression after hypoxia showed a similar increase of expression reflecting same regulatory mechanisms for transcriptional activation ( figure  3b ) . however , both mir-503 and lincrna mir503hg modulations had different effects on ec function ; whereas transfection of mir-503 precursors resulted in negative effects on ec viability ( online figure  4 ) , knockdown of mir503hg suppressed endothelial proliferation independent of  alterations of apoptosis ( figures  3c and 3d , online  figure  4 ) . mir503hg silencing via gapmer technology led to reduced mir-503 expression ( online figure  4 ) . in contrast , transfection of mir-503 precursors did not alter mir503hg expression ( online  figure  4 ) , suggesting dependency of mir-503  expression on mir503hg but not vice versa . migratory capacity of mir503hg - deficient ecs the proliferative and migratory functional defects in ecs after mir503hg silencing were paralleled by a strong up - regulation of the cell - cycle inhibitor p21 ( online figure  4 ) . in line with data from linc00323 - 003 loss - of - function experiments , silencing of mir503hg repressed expression of the key angiogenic transcription factor gata2 ( figure  3f ) . surprisingly , mir503hg repression up - regulated neighboring mir-424 expression ( figure  3 g ) . conclusively , this observation supports a cis - action of lnc - mir503hg on neighboring mir-424 . mir-424 was previously described to be antiproliferative in lung arterial ecs ; moreover , its overexpression triggers antiangiogenic effects in human ecs ( 25 ) . indeed , we were able to validate these findings and found impaired proliferation of human ecs after mir-424 overexpression ( figure  3h ) . however , no significant effects toward impairment of angiogenesis were observed when analyzing capillary tube formation after mir503hg silencing ( online figure  4 ) . intrinsic modulation in arterial ecs had only minor effects on cellular behavior , suggesting a different impact of mir503hg in venous and arterial ecs ( online figure  4 ) . to study the role of enhanced lincrna expression in ecs , the hypoxia - sensitive lincrnas linc00323 - 003 and mir503hg were both overexpressed by generation of stable green fluorescent protein ( gfp)-expressing ec lines ( ea.hy926 ) ( online figure  5 ) . transgenic ea.hy926 constitutively overexpressing linc00323 - 003 revealed improved endothelial healing in the scratch wound assay and showed enhanced cytoprotective hmox1 expression ( online figure  5 ) . in contrast , no changes in endothelial biology were observed after mir503hg overexpression ( online figure  5 ) . to investigate whether the in  vitro findings could be validated in a 3-dimensional ex  vivo model , we generated human induced pluripotent stem cell  derived engineered heart tissues ( ehts ) enriched with gfp - overexpressing huvecs for easy identification of ecs in such human ex  vivo constructs . huvecs showed 99% purity after blasticidine selection , as confirmed by flow cytometric analysis ( data not shown ) and gfp fluorescence microscopy ( figure  4a ) . ehts were transfected with sirna linc00323 - 003 , gapmer mir503hg , or scrambled controls on days 5 , 10 , and 15 of culture , and analyses were performed for eht development and number of ecs . dystrophin staining of cross - sectioned ehts showed a homogenous distribution and high density of cardiomyocytes ( figure  4b ) , which were similarly observed in all groups ( data not shown ) . quantification of gfp - expressing huvecs ( figures  4c to 4 g ) identified a significantly smaller number of ecs in linc00323 - 003 and mir503hg loss - of - function ehts compared with  control tissue constructs . these data suggest that silencing linc00323 - 003 and mir503hg , not only in  vitro but also in an ex  vivo human eht model ,  impairs endothelial biology and tissue vascularization . to identify hypoxia - sensitive endothelial lncrnas , huvecs were first subjected to  24 h of hypoxia . in preliminary experiments , we  found this time point optimal for identifying regulations of a vast majority of lncrnas ( data not shown ) . hypoxia - sensitive noncoding rna expression was detected via 2 approaches , microarray- and rna - seq - based techniques . we first focused on the microarray - derived noncoding rna dataset to search for lncrnas using the following criteria : minimal 4-fold deregulation and intergenic lncrna localization . by this approach , we identified linc00323 ( lnc - dscam-1 ) to be the strongest ( 8-fold ) up - regulated lincrna after hypoxia ( probe uc002yyv ) ( online table  1 ) . rna - seq data identified 773 ( 403 up , 370 down ) significantly deregulated lncrnas ( figure  1a , online table  2 ) . the analysis of rna - seq data for protein - coding genes of huvecs cultured under normoxic or hypoxic conditions showed 8,156 ( 4,032 up , 4,124 down ) significantly deregulated mrnas ( figure  1b , online table  2 ) . the log2-fold expression changes derived from the 2 different technologies were significantly correlated both for lncrnas ( pearson correlation coefficient  = 0.43 , p  < 2.2   10 ) and for  protein - coding genes ( pearson correlation coefficient  = 0.74 , p  < 2.2   10 ) ( online figure  1 ) . rna - seq also confirmed enhanced expression of linc00323 ( lnc - dscam-1 ) under hypoxia ( online table  2 ) . in addition , from the rna - seq data , we identified another hypoxia - sensitive lncrna , mir503hg ( lnc - plac1 - 1 ) , on the basis of the following criteria : 1 ) minimal 4-fold up - regulation ; 2 ) base mean > 1,000 ; and 3 ) intergenic annotation . on the basis of these stringent criteria , we identified lnc - mst1p9 - 2 and lnc - plac1 - 1 as high propriety candidates but omitted lnc - mst1p9 - 2 from further studies because of potential protein - coding properties . subsequent validation experiments confirmed the hypoxia - dependent up - regulation of the previous 2 array- or rna - seq - derived lincrnas , linc00323 and mir503hg ( figure  1c and online figure  1 for other linc00323 transcript isoforms ) . cell compartment specific rna analysis revealed hypoxia - dependent enhanced cytoplasmic linc00323 - 003 expression , whereas mir503hg was increased both in the nuclear and cytoplasmic compartments ( figure  1c ) . high purity of subcellular compartment preparations was proved by screening expression of the nuclear enriched lncrna xist ( online figure  1 ) . endothelial up - regulation of these 2 lncrnas by hypoxia was cell - type specific , as this was not seen in human cardiac fibroblasts or human aortic smooth muscle cells exposed to hypoxia ( online figure  1 ) . the 2 lncrnas were considerably expressed in ecs and vascularized organs , such as kidneys ( data not shown ) . we  next sought to identify potential functional relevance for the identified lncrna candidates in human ecs . linc00323 is encoded on chromosome 21 and has 3 transcript isoforms 21 , 22 according to the lncrna database lncipedia and the ensembl genome browser ( figure  2a ) . we focused on linc00323 transcript variant 3 , as a small interfering rna ( sirna ) approach had obvious effects on ec biology to reduce cell number in  vitro . next to proangiogenic hypoxic signaling , endothelial vegf treatment also increased linc00323 - 003 expression ( figure  2b ) . multiple in  vitro assays were performed to clarify the functional relevance of endothelial linc00323 - 003 expression . because linc00323 - 003 was detectable in nuclear and cytoplasmatic compartments , we used both antisense - mediated sirna ( targeting cytoplasmic lncrnas ) and gapmer ( targeting nuclear lncrnas ) approaches in huvecs . both approaches in a transgenic linc00323 - 003 overexpressing ec line documented potent lncrna silencing ( online figure  2 ) . fluorescein transfection in ecs led to an accumulation in the nucleus ( online figure  2 ) . titration experiments for the sirna chemistry showed detrimental effects on ec viability in a range of 1 to 100 nmol / l sirna , whereas application of 100 pmol / l of sirna exhibited no significant effect ( online figure  2 ) . further sirna experiments were thus performed with 1 nmol / l of sirna to reduce potential off - target effects . both sirna- and gapmer - mediated linc00323 - 003 silencing led to an inhibition of human ec proliferation ( figure  2c , online figure  2 ) , suggesting cytoplasmic and nuclear linc00323 - 003 expression to be critical for endothelial proliferation . in line , linc00323 - 003 silencing increased the ratio of binucleic to total cells and led to an increase in ec size , suggesting proliferation defects ( online figures  2 and 3 ) . accordingly , the cell - cycle inhibitors p21 and p27 were up - regulated , whereas cell - cycle progression - relevant cyclin - dependent kinases 1 and 2 were reduced upon endothelial linc00323 - 003 silencing ( figure  2d , online figure  3 ) . migration capacity was also strongly attenuated by linc00323 - 003 loss ( online figure  3 ) . angiogenic capacity tested by capillary tube formation assays was significantly deteriorated upon linc00323 - 003 silencing ( figure  2e ) . this was paralleled by a repression of  proangiogenic vegfb and induction of the angiogenesis inhibitor thrombospondin ( online figure  3 ) . loss of linc00323 - 003 additionally inhibited proliferation - important extracellular signal  regulated kinase phosphorylation , and both led to a repression of the key endothelial transcription factor gata2 and proangiogenic sirtuin i ( online figure  3 , figure  2f ) . indeed , part of the detrimental actions of  linc00323 - 003 were mediated through gata2 silencing , as genetic overexpression of a  functional gata2 construct attenuated the linc00323 - 003 actions on ecs ( online figure  3 ) . interestingly , linc00323 - 003 silencing reduced gata2 protein but not mrna levels ( figure  2 g ) , suggesting a post - translational mechanism . using starbase 23 , 24 , a bioinformatic - based identification system , we found potential protein candidates interacting with linc00323 - 003 that are also involved in mrna translation and identified the translation initiation  factor eif4a3 . indeed , we were able to immunoprecipitate eif4a3 in human ecs ( figure  2h ) . rna  immunoprecipitation experiments in a stable linc00323 - 003-overexpression ec line revealed significant enrichment of linc00323 - 003 with immunoprecipitated eif4a3 compared with controls ( figure  2i ) . in addition , gata2 mrna was found to be associated with eif4a3 ( figure  2j ) . this suggests a scaffold function of linc00323 - 003 to bind proteins , such as the translation initiation factor eif4a3 ( central illustration ) . linc00323 - 003 silencing also caused impaired proliferative capacity of human coronary artery ecs , suggesting a broad impact of this lncrna on various types of ecs ( online figure  3 ) . the rna - seq - derived lincrna mir503hg is located at chromosome x , harbors a coding sequence of mir-503 , and is adjacent to mir-424 ( figure  3a ) . indeed , analysis of primary mir-503 and mature mir-503 expression after hypoxia showed a similar increase of expression reflecting same regulatory mechanisms for transcriptional activation ( figure  3b ) . however , both mir-503 and lincrna mir503hg modulations had different effects on ec function ; whereas transfection of mir-503 precursors resulted in negative effects on ec viability ( online figure  4 ) , knockdown of mir503hg suppressed endothelial proliferation independent of  alterations of apoptosis ( figures  3c and 3d , online  figure  4 ) . mir503hg silencing via gapmer technology led to reduced mir-503 expression ( online figure  4 ) . in contrast , transfection of mir-503 precursors did not alter mir503hg expression ( online  figure  4 ) , suggesting dependency of mir-503  expression on mir503hg but not vice versa . migratory capacity of mir503hg - deficient ecs was additionally inhibited ( figure  3e ) . the proliferative and migratory functional defects in ecs after mir503hg silencing were paralleled by a strong up - regulation of the cell - cycle inhibitor p21 ( online figure  4 ) . in line with data from linc00323 - 003 loss - of - function experiments , silencing of mir503hg repressed expression of the key angiogenic transcription factor gata2 ( figure  3f ) . additionally , we identified another mirna , mir-424 , genetically neighboring upstream to mir503hg . surprisingly , mir503hg repression up - regulated neighboring mir-424 expression ( figure  3 g ) . conclusively , this observation supports a cis - action of lnc - mir503hg on neighboring mir-424 . mir-424 was previously described to be antiproliferative in lung arterial ecs ; moreover , its overexpression triggers antiangiogenic effects in human ecs ( 25 ) . indeed , we were able to validate these findings and found impaired proliferation of human ecs after mir-424 overexpression ( figure  3h ) . however , no significant effects toward impairment of angiogenesis were observed when analyzing capillary tube formation after mir503hg silencing ( online figure  4 ) . intrinsic modulation in arterial ecs had only minor effects on cellular behavior , suggesting a different impact of mir503hg in venous and arterial ecs ( online figure  4 ) . to study the role of enhanced lincrna expression in ecs , the hypoxia - sensitive lincrnas linc00323 - 003 and mir503hg were both overexpressed by generation of stable green fluorescent protein ( gfp)-expressing ec lines ( ea.hy926 ) ( online figure  5 ) . transgenic ea.hy926 constitutively overexpressing linc00323 - 003 revealed improved endothelial healing in the scratch wound assay and showed enhanced cytoprotective hmox1 expression ( online figure  5 ) . in contrast , no changes in endothelial biology were observed after mir503hg overexpression ( online figure  5 ) . to investigate whether the in  vitro findings could be validated in a 3-dimensional ex  vivo model , we generated human induced pluripotent stem cell  derived engineered heart tissues ( ehts ) enriched with gfp - overexpressing huvecs for easy identification of ecs in such human ex  vivo constructs . huvecs showed 99% purity after blasticidine selection , as confirmed by flow cytometric analysis ( data not shown ) and gfp fluorescence microscopy ( figure  4a ) . ehts were transfected with sirna linc00323 - 003 , gapmer mir503hg , or scrambled controls on days 5 , 10 , and 15 of culture , and analyses were performed for eht development and number of ecs . dystrophin staining of cross - sectioned ehts showed a homogenous distribution and high density of cardiomyocytes ( figure  4b ) , which were similarly observed in all groups ( data not shown ) . quantification of gfp - expressing huvecs ( figures  4c to 4 g ) identified a significantly smaller number of ecs in linc00323 - 003 and mir503hg loss - of - function ehts compared with  control tissue constructs . these data suggest that silencing linc00323 - 003 and mir503hg , not only in  vitro but also in an ex  vivo human eht model ,  impairs endothelial biology and tissue vascularization . hypoxia is a strong proangiogenic stimulus and induces vegf - mediated signaling in ecs ( 19 ) . the present study provides evidence that lncrna expression in ecs is strongly altered by hypoxia . we have identified 2 novel lncrnas , linc00323 - 003 and mir503hg , that are highly sensitive to hypoxia and crucial for endothelial angiogenic characteristics . the mechanisms leading to the hypoxia - mediated regulation of these lncrnas remain to be determined . to this end , we silenced hif1 during hypoxic cell culture of  huvecs and tested effects on linc00323 - 003 and  mir503hg expression . silencing hif1 did not abrogate hypoxia - mediated induction of lncrnas compared with controls ( data not shown ) . this is suggestive of hif1-independent mechanisms of the 2 hypoxia - induced lncrnas described here and is in line  with the encyclopedia of dna elements dataset at  the university of california , santa cruz , showing no  hif1-binding sites in promoter regions of these  lncrnas . both lncrnas have never been described in  endothelial biology , but here we show that they function as crucial factors to control ec behavior . key experiments for linc00323 - 003 were also validated in arterial ecs , suggesting the importance on ecs in general . of translational importance , lncrna knockdown also resulted in impaired vascularization in an ex  vivo induced pluripotent stem cell this model was used because of weak conservation at the sequence level in nonhuman species . however , a potential mouse homologue for mir503hg , gm28730 , with about 70% sequence overlap , could be identified .  the choice to investigate linc00323 - 003 and mir503hg was dependent on their high deregulation in either microarray or rna - seq datasets . it is likely that many other thus far uncharacterized lncrnas also have crucial functions in endothelial biology and should be investigated in future studies ; the database of array- and rna - seq - based lncrna expression profiles reported here will be helpful in this context . both lncrnas linc00323 - 003 and mir503hg exerted an important functional relevance for ec biology , making them potential attractive molecular targets in vascular diseases . we have provided initial insight into their interaction partners , such as mirnas and proteins , but we wish to point out that more in - depth mechanistic studies are needed in the future to fully understand the mode of action of the identified lncrnas . in general , lncrnas are less ( sequence ) conserved among species , thus hampering translational approaches in a relevant in  vivo vascular disease setting in other species models . to circumvent this limitation , we applied a model of human induced pluripotent stem cell  based eht to translate the importance of these 2 lncrnas in endothelial biology in a more realistic translational scenario . both lncrnas linc00323 - 003 and mir503hg exerted an important functional relevance for ec biology , making them potential attractive molecular targets in vascular diseases . we have provided initial insight into their interaction partners , such as mirnas and proteins , but we wish to point out that more in - depth mechanistic studies are needed in the future to fully understand the mode of action of the identified lncrnas . in general , lncrnas are less ( sequence ) conserved among species , thus hampering translational approaches in a relevant in  vivo vascular disease setting in other species models . to circumvent this limitation , we applied a model of human induced pluripotent stem cell  based eht to translate the importance of these 2 lncrnas in endothelial biology in a more realistic translational scenario . we have identified 2 novel hypoxia - sensitive endothelial lncrnas , linc00323 - 003 and mir503hg , by the use of microarray and next - generation rna - seq techniques . functional characterization applying loss- and gain - of - function approaches in cultured ecs  revealed an important role for both of these lncrnas in endothelial biology . our data enable the future development of novel lncrna - therapeutic approaches to cardiovascular diseases . more general , our data identify novel strategies based on lncrna modulation to alter tissue vascularization , with the aim of either enhancing ( e.g. , in ischemic tissues ) or  blocking ( e.g. , in vessel - dependent cancers ) vascularization.perspectivescompetency in medical knowledge : angiogenesis is a key mechanism by which organs maintain blood supply , and this has therapeutic implications for amelioration of ischemia in organs or inhibition of vessel - dependent cancers . lncrnas are key regulators of endothelial proliferation and play a role in angiogenesis.translational outlook : future research should examine the potential role of interventions that increase or normalize lncrna expression and cell type  specific function to modulate angiogenesis in patients with myocardial infarction , peripheral arterial disease , or ischemic stroke . competency in medical knowledge : angiogenesis is a key mechanism by which organs maintain blood supply , and this has therapeutic implications for amelioration of ischemia in organs or inhibition of vessel - dependent cancers . translational outlook : future research should examine the potential role of interventions that increase or normalize lncrna expression and cell type  specific function to modulate angiogenesis in patients with myocardial infarction , peripheral arterial disease , or ischemic stroke .