. Author manuscript; available in PMC: 2013 Dec 1.

Published in final edited form as: Physiol Rev. 2011 Jan;91(1):10.1152/physrev.00047.2009. doi: 10.1152/physrev.00047.2009

TABLE 3.

In vivo correlations of in vitro responses of EC signaling and gene expression to disturbed flow at athero-prone and poststenotic areas

Signaling/Genes and Products (Expression or Activity)	In vitro					In vivo

	Effect of Reciprocating or Low Flow (Versus Laminar or Pulsatile)	Model	Stimulus		Reference Nos.	Response (Versus Straight Segment or Control Vessel)	Segment	Animal/Subject	Refs.

			Flow type: dyn/cm²	Duration (h)
Inflammation
ICAM-1	Increased	HUVEC in parallel-plate chamber	PF: 5 ± 5	24	72	Profound focal expression in the outer wall of the internal carotid artery and advanced lesions	Carotid artery	Patients	168
ICAM-1	Increased	HUVEC in parallel-plate chamber	RF: ± 5	24	72		Carotid artery	Patients	168
	Increased	EC in orbital shaker/parallel-plate chamber	LF: 14	6	119	Highly expressed at lesion-prone sites	Aortas	C57BL/6 mice	269
			Orbital: 4–12 (96–210 rpm)				Aortas	Rabbits
							Ascending aorta and proximal arch	LDLR^−/− mice
							Aortic arch	ApoE^−/− mice
	Increased	BAEC in flow channel	PF: 50 ± 40	4	257	Highly expressed at lesion-prone sites	Aortic sinus, ascending aorta, aortic arch, and abdominal aorta	C57BL/6 mice	407
	Increased	BAEC in flow channel	RF: ± 2.6	4	257	Highly expressed at lesion-prone sites		ApoE^−/− mice	407
	Increased	HAEC in cone-and-plate viscometer	RF: ± 5	24	536	Increased by disturbed flow induced by partial ligation	Carotid artery	C57BL/6 mice	410
								ApoE^−/− mice
								p47^phox−/−mice
								p47^phox−/−/ApoE^−/− mice
	Increased	HAEC in cone-and-plate viscometer	LF: 5, 15	24	537	Highly expressed at lesions	Coronary artery	Patients	536
	Increased	HAEC in cone-and-plate viscometer	RF: ± 5	24	537	Highly expressed in lesser curvature and orifices of arch branches	Aortic arch	C57BL/6 mice	552
VCAM-1	Increased	HAEC in disturbed flow/parallel-plate chamber	LF: 13	24	50	Expressed at advanced lesions	Carotid artery	Patients	168
VCAM-1	Increased	HAEC in disturbed flow/parallel-plate chamber	Recirculation:< 0.01	24	50	Expressed at advanced lesions	Carotid artery	Patients	168
	Increased	HUVEC in parallel-plate chamber	PF: 5 ± 5	24	72	Highly expressed at lesion-prone sites	Aortas, Ascending aorta and proximal arch, Aortic arch	C57BL/6 mice	269
			RF: ± 5					Rabbits
								LDLR^−/− mice
								ApoE^−/− mice
	Increased	HUVEC in cone-and-plate viscometer	Athero-prone versus atheroprotective patterns form human carotid	24	115	Highly expressed at lesion-prone sites	Aortic sinus, ascending aorta, aortic arch, and abdominal aorta	C57BL/6 mice	407
	Increased	HUVEC in cone-and-plate viscometer		24	115	Highly expressed at lesion-prone sites		ApoE^−/− mice	407
	Increased	HUVEC in cone-and-plate viscometer	Athero-prone versus atheroprotective patterns from human circulation	24	239	Increased by disturbed flow induced by partial ligation	Carotid artery	C57BL/6 mice	410
								ApoE^−/− mice
								p47^phox−/− mice
								p47^phox−/−/ApoE^−/− mice
Highly expressed in lesser curvature and orifices of arch branches	Aortic arch	C57BL/6 mice	552
Increased expression with reduced flow by ligation	Carotid artery	Rabbits	596
E-selectin	Increased	HAEC in disturbed flow/parallel-plate chamber	LF: 13	24	52	Expressed at advanced lesions	Carotid artery	Patients	168
E-selectin	Increased	HAEC in disturbed flow/parallel-plate chamber	Recirculation: <0.01	24	52	Expressed at advanced lesions	Carotid artery	Patients	168
	Increased	HUVEC in parallel-plate chamber	PF: 5 ± 5	24	72
	Increased	HUVEC in parallel-plate chamber	RF: ± 5
	Increased	EC in orbital shaker/parallel-plate chamber	LF: 14	6	119
	Increased	EC in orbital shaker/parallel-plate chamber	Orbital: 4–12 (960–210 rpm)	6	119
MCP-1	Increased	BAEC in flow channel	PF: 50 ± 40	4	257	Highly expressed near the intercostal artery orifices	Descending aorta	Rats	86
	Increased	BAEC in flow channel	RF: ± 2.6	4	257
	Increased	BAEC in flow channel	LF: 25	4, 8	265
	Increased	BAEC in flow channel	RF: ± 3	4, 8	265
BMPs or their antagonists	Increased	BAEC/HCAEC in cone-and-plate viscometer	LF: 15	24	71	Highly expressed at lesions	Carotid artery	Patients	46
BMPs or their antagonists	Increased	BAEC/HCAEC in cone-and-plate viscometer	RF: ± 5	24	71	Highly expressed at lesions	Carotid artery	Patients	46
	Increased	MAEC in cone-and-plate viscometer	LF: 5, 15	24	537	Coexpression of BMP-4 and the antagonists follistatin, noggin, and matrix Gla protein	Aortic arch and thoracic aorta	C57BL/6 mice	71
		RF: ±5					Coronary artery		71
		RF: ±5					Coronary artery		Patients
						Sustained immunoreactivity of matrix Gla protein at lesions	Abdominal aorta	Patients	151
						Increased for BMP-4 by disturbed flow induced by partial ligation	Carotid artery	C57BL/6 mice	410
								ApoE^−/− mice
								p47^phox−/− mice
								p47^phox−/−/ApoE^−/− mice
						Highly expressed at lesions	Coronary artery	Patients	537
TLR-2	Increased	HCAEC in step flow chamber	LF: >5	12	161	Highly expressed in lesser curvature	Aortic arch	LDLR^−/− mice	399
	Increased	HCAEC in step flow chamber	Recirculation	12	161	Atheroprotective by TLR2 deficiency	Aortic arch	TLR2^−/− mice	399
JNK	Increased	BAEC in parallel-plate chamber	LF: 12	18	229	Higher phosphor. in lesser curvature versus greater curvature of aortic arch	Aortic arch	C57BL/6 mice	229
			RF: 0.6 ± 1.92			Higher phosphor. in carotid sinus versus straight segments		ApoE^−/− mice
			RF: 0.6 ± 1.92			Higher phosphor. in carotid sinus versus straight segments	Carotid artery
HuR	Increased	HUVEC in cone-and-plate	LF: 15	24	487	Increased in lesser curvature versus greater curvature of aortic arch, and by disturbed flow induced by partial carotid ligation	Aorta arch	C57BL/6 mice	487
HuR	Increased	HUVEC in cone-and-plate	RF: ± 5	24	487		Carotid artery	C57BL/6 mice	487
Oxidative stress
Superoxide, NAD(P)H oxidase, H₂O₂, orperoxynitrite	Increased	HUVEC in parallel-plate chamber	LF: 5	1, 5, 24	138	Positive nitrotyrosine staining (an indicator of peroxynitrite) in bifurcations and curvatures	Coronary artery	Patients	258
	Increased	HUVEC in parallel-plate chamber	RF: ± 5	1, 5, 24	138
	Increased	BAEC in a flow channel	LF: 23	4	258
	Increased	BAEC in a flow channel	RF: 0.02 ± 3	4	258
	Increased	BAEC in flow channel	LF: 25	4, 8	266
	Increased	BAEC in flow channel	RF: ± 3	4, 8	266
	Increased (Xanthine oxidase)	BAEC/MAEC in cone-and-plate viscometer	LF: 15	4	374
	Increased (Xanthine oxidase)	BAEC/MAEC in cone-and-plate viscometer	RF: ±15	4	374
GTPCH-1	Decreased	HAEC/HUVEC in cone-and-plate viscometer	LF: 15	14	335	Decreased by disturbed flow induced by partial ligation	Carotid artery	C57BL/6 mice	335
GTPCH-1	Decreased	HAEC/HUVEC in cone-and-plate viscometer	RF: ± 15	14	335	Decreased by disturbed flow induced by partial ligation	Carotid artery	C57BL/6 mice	335
Regulation of endothelial integrity/apoptosis
XBP-1	Increased	HUVEC in parallel-plate chamber	LF: 12	24	647	Highly expressed in branch curve and lesion areas	Aortas	ApoE^−/− mice	647
XBP-1	Increased	HUVEC in parallel-plate chamber	RF: ± 4.5	24	647	Highly expressed in branch curve and lesion areas	Aortas	ApoE^−/− mice	647
Tie1	Increased	BAEC in a parallel-plate/step flow chamber	LF:12	16	469	Up-regulated at the (1) femoral artery and its branches, (2) aorta-renal artery junction, (3) inner aspect of the cup-shaped cusps in the aortic side of aortic valve, (4) atherosclerotic lesions in the abdominal aorta, (5) downstream of the A/V junction in vein interposition grafts, and (6) region of flow obstruction in aneurysms.	Femoral artery, aorta-renal artery junction,	tie1-lacZ transgenic rats,	469
			Recirculation				aortic valve,	tie1-lacZ transgenic mice,
							abdominal aorta,	ApoE^−/− mice
							vein interposition grafts,
							aneurysms
HDAC3	Increased	HUVEC in orbital shaker	0–20 with mean of 4.5 at 0.5Hz	24	643	Increased in areas in close vicinity to branching openings	Aortas	ApoE^−/− mice	643
Regulation of endothelial permeability
PAK	Increased	BAEC in parallel-plate flow chamber/cone-and-plate viscometer	LF: 12	4	440	PAK activity correlates with VCAM-1 expression, FN deposits, and vascular permeability	Carotid artery,	ApoE^−/− mice	440
	Increased		Athero-prone versus atheroprotective patterns from human carotid	4	440		Aortic arch	ApoE^−/− mice	440
Cx43	Increased	BAEC in step flow channel	LF: 13.5	5, 16	147	Abundant at downstream edge of the ostia of branching vessels and at flow dividers	Aortas	Rats	195
	Increased	BAEC in step flow channel	Recirculation: 0–8.5	5, 16	147		Aortas	Rats	195
						Highly expressed at lesions	Aortic arch	LDLR^−/− mice	314
						Highly expressed at lesions	Carotid artery	Patients	314
Regulation of EC migration
Ang-2	Increased	HUVEC/HMEC/BAEC in cone-and-plate viscometer	LF: 5, 15	24	574	Increased in lesser curvature versus greater curvarure of aortic arch	Aortic arch and thoracic aorta	C57/BL6J mice	574
	Increased	HUVEC/HMEC/BAEC in cone-and-plate viscometer	RF: ± 5, ± 15	24	574		Aortic arch and thoracic aorta	C57/BL6J mice	574
Regulation of SMC proliferation and migration
PDGF-A, -B or receptors	Increased by TF versus LF and PF,	BAEC in cone-and-plate viscometer	LF: 15, 36	6	361	Increased	Carotid artery	Patients	616
	Decreased by LF versus static		TF: 15 ± 0.90
	Decreased by LF versus static		PF: 12 ± 0.06–18 ± 0.29
PDGF-DD	Increased	HUVEC/HUVSMC in cone-and-plate viscometer	Athero-prone versus atheroprotective patterns from human carotid	24	566	Increased at lesions	Aortic arch	ApoE^−/− mice	566
Regulation of ECM
Cathepsin K	Increased	MAEC in cone-and-plate viscometer	LF: 15	24	461	Positive correlation with elastic lamina fragmentation	Coronary arteries with various degrees of plaques	Patients	461
	Increased	MAEC in cone-and-plate viscometer	RF: ± 5	24		Positive correlation with elastic lamina fragmentation	Coronary arteries with various degrees of plaques	Patients	461
MMP-9	Increased	Perfused left common porcine carotids ex vivo	PF: 0.3 ± 0.1, 6 ± 3	72	200	Increased by flow cessation by ligation	Carotid artery	C57BL/6J mice	218
	Increased	Perfused left common porcine carotids ex vivo	RF: 0.3 ± 3	72	200	Increased by flow cessation by ligation	Carotid artery	C57BL/6J mice	218
	Increased	MLEC/HUVEC in cone-and-plate viscometer	LF: 15	6	357
	Increased	MLEC/HUVEC in cone-and-plate viscometer	RF: ±15	6	357
MMP-2	Increased	Perfused left common porcine carotids ex vivo	PF: 0.3 ± 0.1, 6 ± 3	72	200	Increased by reduction in flow by partial outflow occlusion in injured right common carotid artery	Carotid artery	New Zealand White male rabbits	29
	Increased	Perfused left common porcine carotids ex vivo	RF: 0.3 ± 3	72	200		Carotid artery	New Zealand White male rabbits	29
Vasodilator
eNOS	Decreased	Perfused left common porcine carotids ex vivo	PF: 0.3 ± 0.1, 6 ± 3	72	199	Low expression at poststenotic sites	Carotid artery constriction	eNOS-GFP transgenic mice	83
	Decreased	Perfused left common porcine carotids ex vivo	RF: 0.3 ± 3	72	199	Low expression at poststenotic sites	Carotid artery constriction	eNOS-GFP transgenic mice	83
	Decreased	BAEC in flow channel	LF: 23	4, 8	258	Decreased by disturbed flow induced by partial ligation	Carotid artery	C57BL/6 mice	410
			RF: 0.02 ± 3					ApoE^−/− mice
								p47^phox−/− mice
								p47^phox−/−/ApoE^−/− mice
	Decreased	BAEC in flow channel	LF: 25	4, 8	265
	Decreased	BAEC in flow channel	RF: ± 3	4, 8	265
	Decreased	Perfused BAEC tubes	LF: 10	4	474
	Decreased	Perfused BAEC tubes	RF: 10 ± 10	4	474
	Decreased	Perfused BAEC tubes	PF: 6 ± 3	4, 24	526
	Decreased	Perfused BAEC tubes	RF: 0.3 ± 3	4, 24	526
	Decreased	Perfused EAhy 926 tubes	PF: 6 ± 3	24	527
	Decreased	Perfused EAhy 926 tubes	RF: 0.3 ± 3	24	527
	Decreased	HAEC in cone-and-plate viscometer	LF: 15	14	615
	Decreased	HAEC in cone-and-plate viscometer	RF: ± 15	14	615
	Decreased	Perfused BAEC tubes	PF: 6 ± 3	1, 4, 24	653
	Decreased	Perfused BAEC tubes	RF: 0.3 ± 3	1, 4, 24	653
Complement inhibitory protein
CD59	Decreased versus LF and no induction versus static	HUVEC/HAEC in parallel-plate chamber	LF: 12	24, 48	296	Lower expression at lesser curvature of aortic arch compared with straight segments	Aortas	Murine	296
	Decreased versus LF and no induction versus static	HUVEC/HAEC in parallel-plate chamber	RF: ±5	24, 48	296		Aortas	Murine	296
Signal transduction
AMPK	Decreased	BAEC in parallel-plate chamber	LF: 12	8	228	Lower expression at aortic arch than thoracic aorta	Aorta arch	C57BL/6J mice	228
	Decreased	BAEC in parallel-plate chamber	RF: 1 ± 5	8	228	Lower expression at aortic arch than thoracic aorta	Thoracic aorta	C57BL/6J mice	228
p70S6K	Increased	BAEC in parallel-plate chamber	LF: 12	8	228	Higher expression at aortic arch than thoracic aorta	Aorta arch	C57BL/6J mice	228
	Increased	BAEC in parallel-plate chamber	RF: 1 ± 5	8	228	Higher expression at aortic arch than thoracic aorta	Thoracic aorta	C57BL/6J mice	228
MKP-1	Increased by LF versus static	HUVEC in parallel-plate chamber	LF: 12	24, 48	642	Lower expression in lesser curvature than greater curvature, Sparing of lesions in MKP-1^−/− mice	Aortas	C57BL/6 mice	642
	Increased by LF versus static	HUVEC in parallel-plate chamber	LF: 12	24, 48	642		Aortas	MKP-1^−/− mice	642
Shc	Increased	BAEC in parallel-plate chamber	LF: 12	18	350	Higher phosphor. at aortic arch compared with straight ascending aorta	Aortas	C57BL/6 mice	350
	Increased	BAEC in parallel-plate chamber	RF: ±6.5	18	350		Aortas	C57BL/6 mice	350
Transcription factor
KLF-2	Decreased	HUVEC in cone-and-plate viscometer	Athero-prone versus atheroprotective patterns from human carotid	24	444	Low expression at branches and poststenotic sites	Abdominal aorta bifurcation, common iliac artery, carotid artery bifurcation, aortic arch, carotid artery constriction	Patients	145
	Decreased	HUVEC in cone-and-plate viscometer		24	444	Low expression at branches and poststenotic sites		ApoE^−/− mice	145
	Decreased	HUVEC in parallel-plate chamber	PF: 12 ± 4	24	600	Decreased by disturbed flow induced by partial ligation	Carotid artery	C57BL/6 mice	410
			RF: 0.5 ± 4					ApoE^−/− mice
								p47^phox−/− mice
								p47^phox−/−/ApoE^−/− mice
						No or low expression at branches and poststenotic sites	Abdominal aorta and celiac artery, Abdominal aorta constriction	Rats	600
Nrf2	Decreased	HUVEC in cone-and-plate viscometer	Athero-prone versus atheroprotective patterns from human carotid	24	116	Decreased Nrf2 nuclear localization in endothelium in lesser curvature of the arch versus straight portion of thoracic aorta	Aortic arch and thoracic aorta.	C57BL/6 mice	116
NF-κB	Increased	HUVEC in cone-and-plate viscometer	Athero-prone versus atheroprotective patterns from human carotid	24	115	Activated at fibrotic-thickened intima/media and atheromatous areas of lesion	Atherosclerotic aortas, normal arteries, veins	Patients	48
	Increased	HUVEC in cone-and-plate viscometer	Athero-prone versus atheroprotective patterns from human circulation	24	239	Highly expressed at lesion-prone sites	Ascending aorta and arch	C57BL/6 mice	234
	Increased	HUVEC in cone-and-plate viscometer		24	239	Highly expressed at lesion-prone sites	Ascending aorta and arch	LDLR^−/− mice	234
	Increased by 2 versus 16 (dyn/cm²)	HAEC in parallel-plate chamber	LF: 2, 16	0.5–24	387	Robust p65 localization in lesser curvature versus greater curvature	Aortic arch	ApoE^−/− mice	239
	Increased	BAEC/HUVEC in parallel-plate chamber	LF: 12	18	437	Activated (inhibited by PAK-Nck blocking peptides)	Carotid sinuses	C57BL/6 mice	437
	Increased	BAEC/HUVEC in parallel-plate chamber	RF: 1 ± 12	18	437	Activated in experimental hypercholesterolemia	Coronary arteries	Pigs	629
Egr-1	Increased	HUVEC in step flow chamber	LF:12		405	Highly expressed at lesions	Carotid artery,	Patients	369
	Increased	HUVEC in step flow chamber	Recirculation		405	Highly expressed at lesions	Aortas	LDLR^−/− mice	369
Others
Heat shock protein 60	Decreased by low shear versus high shear.	HUVEC in cone-and-plate viscometer	LF: 0–50	24	252	Lower expression in reduced shear versus increased shear regions by ligation	Carotid artery	Lewis rats	252

BAEC, bovine aortic endothelial cell; HAEC, human aortic endothelial cell; HCAEC, human coronary artery endothelial cell; HMEC, human microvascular endothelial cell; HUVEC, human umbilical vein endothelial cell; HUVSMC, human umbilical vein smooth muscle cell; MAEC, mouse aortic endothelial cell; MLEC, murine lymphoid endothelial cell; LF, laminar flow; RF, reciprocating flow; PF, pulsatile flow; TF, turbulent flow; FN, fibronectin.