The Endothelial Barrier Restricts Endocrine Actions to the Luminal Vascular Receptors: Changing the Paradigm: A Didactic Approach


  •   Rafael Rubio


In 1849, the first list of endocrine hormones was discovered and proposed that the synthesizing gland delivers it to the circulation.  The circulatory hormone reaches the target organ, physically unimpeded acts directly on the parenchymal cells. Such a simplistic view persists despite new knowledge of an endothelial wall barrier and implications for every parenchymal cell in the body. This misconception leads to inadequate interpretations of data, wrong diagnosis and therapeutic expectations, erroneous hypotheses, and misleads further research work. The quest of this review is to play down this misconception by pointing out key overlooked findings of the vascular endothelial wall: 1) The selective endothelial barrier physically separates two same-hormone-containing compartments; the endocrine and the interstitial autocrine hormone compartments, 2) the hormone concentrations values in these compartments are independent of each other, 3) in each compartment the hormone acts solely on the receptors of that particular compartment, 4) multiple intravascular endocrine hormones act solely on their corresponding luminal endothelial membrane receptor (LEMR), without directly acting on the parenchymal cells, 5) Agonist-activation of LEMR triggers the release of specific paracrine endothelial agents that in conjunction with autocrine interstitial hormone modulate parenchymal function(s) and perhaps the turnover of the interstitial autocrine hormone, 6) these hormone compartments, functionally interact via paracrine exchange signaling, and the integrated intercourse of all these events result in the final hormonal organ effect. The present challenges to achieving more rationale therapeutic effects are to design agonists or antagonists that exclusively gain access to a target compartment and have high specificity for the receptor of the cells in that compartment.

Keywords: Autocrine hormones, organ compartments, paracrine signaling


Berthold AA. Lehrbuch der Phsiologie des Menschen und der Thiere (1 ed.). Göttingen: Vandenhoek und Ruprecht; 1829.

Armstrong KJ., Noall MW., Stouffer JE. Dextran-linked insulin: a soluble high molecular weight derivative with biological activity in vivo and in vitro. Biochem. Biophys. Res. Commun. 1972; 47: 354–360.

Balcells E., Suarez J., Rubio R. The functional role of intravascular coronary endothelial adenosine receptors. Eur. J. Pharmacol. 1992; 210: 1–9.

Balcells E., Suarez J., Rubio R. Implications of the coronary vascular endothelium as a mediator of the vasodilatory and dromotropic actions of adenosine. J. Mol. Cell. Cardiol. 1993; 25: 693–706.

Ceballos G., Rubio R. Endothelium‐mediated negative dromotropic effects of intravascular acetylcholine. Eur. J. Pharmacol. 1988; 362: 157–166.

Rubio R., Ceballos G., Balcells E. Intravascular adenosine: the endothelial mediators of its negative dromotropic effects. Eur J Pharmacol. 1999; 370: 27–37.

Rubio R., Ceballos C. Functional implications of sole and selective activation of intravascular coronary endothelial hormonal receptors. Acta Pharmacologica Sinica. 2000; 21: 577-586.

Nees S., Herzog V., Becker BF., Bock M., Des Rosiers C., Gerlach E. The coronary endothelium: a highly active metabolic barrier for adenosine. Res. Cardiol. 1985; 80: 515.

Olsson RA., Davis CJ., Khouri EM., Paterson ER. Evidence for an adenosine receptor on the surface of dog coronary myocytes. Circ. Res. 1976; 39: 93–98.

Schrader J., Nees S., Gerlach E. Evidence for a cell surface adenosine receptor on coronary myocytes and atrial muscle cells. Pflueger’s Arch. 1977; 369: 251–257.

Bevan JA., Duckles SP. Evidence for alpha-adrenergic receptors on intimal endothelium. Blood Vessels 1975; 12: 307–310.

Castillo-Hernández J., Rubio R., Maldonado-Cervantes MI. A limited vs a transient AT1R internalization indicates that distinct mechanisms of AT1R activation are possible. Faseb. 2021; 35: 2021.

Castillo-Hernandez JR., Rubio-Gayosso I., Sada-Ovalle I., Garcia- Vazquez A., Ceballos G., Rubio R. Intracoronary Angiotensin II causes inotropic and vascular effects via different paracrine mechanisms. Vasc. Pharmacol. 2004; 41: 147–158.

Castillo-Hernandez JR., Torres-Tirado D., Barajas-Espinosa A., Chi-Ahumada E., Ramiro-Diaz J., Ceballos G., et al. Two dissimilar AT1 agonists distinctively activate AT1 receptors located on the luminal membrane of the coronary endothelium. Vasc. Pharmacol. 2009; 51: 314–322.

Ceballos G., Figueroa L., Rubio I., Gallo G., Garcia A., Martinez A., et al. Acute and nongenomic effects of testosterone on isolated and perfused rat heart. J Cardiovasc Pharmacol. 1999; 33: 691–7.

Rubio R., Ceballos G., Sole activation of three luminal adenosine receptor subtypes in different parts of the coronary vasculature. Am. J. Physiol. Heart Circ. Physiol. 2003; 284: H204–H214.

Rubio R., Torres-Tirado D., Castillo-Hernández J., Chi-Ahumada E., Ramiro-Diaz J. The coronary endothelium behaves as a selective functional diffusion barrier for intravascular Angiotensin II. Vasc. Pharmacol. 2013; 58: 54-63.

Torres-Tirado D., Ramiro-Diaz J., Knabb M., Rubio R. The molecular weight of different angiotensin II polymers directly determines the density of endothelial membrane receptors and coronary vasoconstriction. Vasc. Pharmacol. 2013; 58: 346-355.

Zenteno ST., Ceballos G., Rubio R. Effects of arginine vasopressin in the heart are mediated by specific intravascular endothelial receptors. Europ. J. Pharmacol. 2000; 410: 15-23.

Dostal DE., Baker KM. The Cardiac Renin-Angiotensin System; Conceptual, or a Regulator of Cardiac Function? Circ Res. 1999; 85: 643-650.

Nyui N., Tamura K., Mizuno K., Ishigami T., Hibi K. Strecth-induced MAP kinase activation in cardiomyocytes of angiotensinogen-deficient mice. Biochem and Biophysc Res Comm. 1997; 235: 36-41.

Salas M., Vila-Petroff M., Palomeque J., Aiello E., Mattiazzi A. Positive inotropic and negative lusitropic effect of angiotensin II: intracellular mechanisms and second messengers. J. Mol. Cell. Cardiol. 2001; 33: 1957–1971.

Figueroa-Valverde L., Luna H., Castillo-Henkel C., Munoz-Garcia O., Morato-Cartagena T., Ceballos-Reyes G. Synthesis and evaluation of the cardiovascular effects of two, membrane impermeant, macromolecular complexes of dextran-testosterone. Steroids. 2002; 67: 611–619.

Rodriguez-Hernandez A., Rubio-Gayosso I., Ramirez I., Ita-Islas I., Meaney E., Gaxiola S. et al. Intraluminal-restricted 17β-estradiol exerts the same myocardial protection against ischemia/reperfusión injury in vivo as free 17β-estradiol. Steroids. 2008; 73: 528–538.

Sierra-Ramirez A., Morato T., Campos R., Rubio I., Calzada C., Mendez E., et al. Acute effects of testosterone on intracellular Ca2+ kinetics in rat coronary endothelial cells are exerted via aromatization to estrogens. Am J Physiol. 2004; 287: H63–71.

Kawada T., Yamazaki T., Akiyama T., Li M., Zheng C., Shishido T., Mori H., Sugimachi M. Angiotensin II attenuates myocardial interstitial acetylcholine release in response to vagal stimulation. Am. J. Physiol. 2007; 293: H2516–H2522.

Dell'Itali LJ., Meng QC., Balcells E., Wei CC., Palmer R., Hageman GR., Durand J., Hankes GH., Oparil S. Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces. J. Clin. Invest. 1997; 100: 253–258.

Gidday JM., Rubio R., Berne RM. Increases in coronary flow by intracoronary adenosine occur independently of changes in interstitial fluid adenosine. Physiologist. 1987; 30: 187.

Gidday JM., Hill HE., Rubio R., Berne RM. Estimates of left ventricular interstitial fluid adenosine during catecholamine stimulation. Am. J. Physiol. 1988; 254: H207-H216.

Heller L., Morman D. 1988, Estimates of interstitial adenosine from surface exudates of isolated rat hearts. J. Mol. Cell. Cardiol. 1988; 20: 509.

Lasley RD., Hegge JO., Noble MA., Mentzer RM. Comparison of interstitial fluid and coronary venous adenosine levels in vivo porcine myocardium. J. Mol. Cell. Cardiol. 1998; 30: 1137–1147.

Navar LG., Kobori H., Prieto MC., Gonzalez-Villalobos RA. Intratubular Renin-Angiotensin System in Hypertension. Hypertension. 2011; 57: 355–362.

Akira N., Seth DM., Navar LG. Renal Interstitial Fluid Concentrations of Angiotensins I and II in Anesthetized Rats. Hypertension. 2020; 39: 129-134.

Rafael R., Knabb M. The luminal endothelial membrane-glycocalyx; functionalities in health and disease. Morgan and Claypool, Science Publishers; 2017.

Siragy HM., Howell NL., Ragsdale NV., Carey RM. Renal interstitial fluid angiotensin. Modulation by anesthesia, epinephrine, sodium depletion, and renin inhibition. Hypertension. 1995; 25: 1021–1024.

Tietjan CS., Tribble CG., Gidday JM., Philips CM., Belardinelli L., Rubio R., Berne RM. Interstitial adenosine in guinea pig hearts: an index obtained by epicardial disks. Am. J. Physiol. 1990; 259: H1471-H1476.

Chih-Chang W., Lucchesi PA., Tallaj J., Wayne E. Bradley WE., Powell PC., Dell’Italia LJ. Cardiac interstitial bradykinin and mast cells modulate the pattern of LV remodeling in volume overload in rats. Am J Physiol. 2003; 285: H784–H792.

Furchgott R., Zawadzki, J. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288: 373–376.

Frangos JA. Flow effects on endothelial cell signal transduction, function, and mediator release. New York: Oxford Univ. Press; 1995.

White CR., Frangos JA. The shear stress of it all: The cell membrane and mechanochemical transduction. Phil Trans R Soc. 2007; 362: 1459–1467.

Taylor AE., Granger DN. Exchange of macromolecules across the microcirculation. Handbook of Physiology; 1984.

Haga, K., Haga, T. Affinity chromatography of the muscarinic acetylcholine receptor. J. Biol. Chem. 1983; 258: 13575– 13579.

Arroyo-Flores B., Chi-Ahumada E., Erika Briones-Cerecero E., Barajas-Espinosa A., Perez-Aguilar S., et al. Cardiac Ischemia and Ischemia/Reperfusion Cause Wide Proteolysis of the Coronary Endothelial Luminal Membrane: Possible Dysfunctions. The Open Cardiovascular Medicine Journal. 2011; 5: 001-007

Perez-Aguilar S., Torres-Tirado D., Martell-Gallegos G., Velarde-Salcedo J., Barba-de la Rosa A. P., Knabb M., et al. G protein-coupled receptors mediate coronary flow- and agonist-induced responses via lectin-oligosaccharide interactions. Am J Physiol Heart Circ Physiol. 2014, 306: H699–H708.

Torres-Tirado D., Knabb M., Castaño I., Patrón-Soberano A., De Las Peñas A., Rubio R. Candida glabrata binds to glycosylated and lectinic receptors on the coronary endothelial luminal membrane and inhibits flow sense and cardiac responses to agonists. Am J Physiol. 2016; 310: R24–R32.

De Godoy MA., Rattan S. Translocation of AT1- and AT2 receptors by higher concentrations of angiotensin II in the smooth muscle cells of rat internal anal sphincter. J. Pharmacol. Exp. Ther. 2006; 319: 1088-1095.

Drake MT., Shenoy SK., Lefkowitz RJ. Trafficking of G protein-coupled receptors. Circ. Res. 2006; 99: 570–582.

Koening J., Edwardson M. Endocytosis and recycling of G protein-coupled receptors. Trends Pharmacol. Sci. 1997; 18: 276–287.

Olivares-Reyes AJ., Smith RD., Hunyady L., Shah BH., Catt KJ. Agonist-induced Signaling, Desensitization, and Internalization of a Phosphorylation-deficient AT1A Angiotensin Receptor. L. Biol. Chem. 2001; 276: 37761–37768.

Toth D., Toth J., Gulyas G., Balla A., Balla T., Hunyady L., Varnai P. Acute depletion of plasma membrane phosphatidylinositol 4,5-bisphosphate impairs specific steps in endocytosis of the G-protein coupled receptor. J. Cell Sci. 2012; 125: 2185–2197.

Franco M., Bautista-Pérez R., Cano-Martínez A., Pacheco U., Santamaría J., del Valle Mondragón L., et al. Physiopathological implications of P2X1 and P2X7 receptors in regulation of glomerular hemodynamics in angiotensin II-induced hypertension. Am J Physiol Renal Physiol. 2017; 313: F9 –F19.

Graciano ML., Nishiyama A., Jackson K., Seth DM., Ortiz RM., Prieto-Carrasquero M., et al. Purinergic receptors contribute to early mesangial transformation and renal vessel hypertrophy during angiotensin II-induced hypertension. Am J Physiol. 2008; 294: F161–F169.

Ji X., Naito Y., Hirokawa G., Weng H., Hiura Y., Takahashi R., et al. P2X(7) receptor antagonism attenuates hypertension and renal injury in Dahl salt-sensitive rats. Hypertens Res. 2012; 35: 173–179.

Larner J., Allan G., Kessler C., Reamer P., Gunn R., Huang LC. Phosphoinositol glycan derived mediators and insulin resistance. Prospects for diagnosis and therapy. J Basic Clin Physiol Pharmacol. 1998; 9: 127-137.

Booz DW., Dostal DE., Baker KM. Paracrine actions of cardiac fibroblasts on cardiomyocytes: implications for the cardiac renin-angiotensin system. Am. J. Cardiol. 1999; 83: 44-47.

Chiu JD., Richey JM., Harrison LN., Zuniga E., Kolka CM., Kirkman E., et al. Direct Administration of Insulin into Skeletal Muscle reveals That the Transport of Insulin Across the capillary endothelium Limits the Time Course of Insulin o Activate Glucose Disposal. Diabetes.2008; 57: 828-833.

Kolka CM. The vascular endothelium plays a role in insulin action. Clin Exp Pharmacol Physiol. 2020; 47: 168-175.

Kolka CM., Bergman RN. The Barrier Within Endothelial Transport of Hormones. Physiology. 2012; 27: 237–247.

Schnermann J. Concurrent Activation of Multiple Vasoactive Signaling Pathways in Vasoconstriction Caused by Tubulo-glomerular Feedback: A Quantitative Assessment. Ann Rev Physiol. 2015; 77:301-322.

Schnermann J., Levine DZ. Paracrine factors in tubule-glomerular feedback: adenosine, ATP, and nitric oxide. Ann Rev Physiol. 2003; 65: 501-529.

Stolwijk JA., Zhang X., Gueguinou M., Zhang W., Matrougui K. Regulation of endothelial barrier function. J Biol Chem. 2016; 291: 22894–22912.

Speth RC., Giese MJ. Update on the Renin-Angiotensin System. J. Pharmacol, & Clinic. Toxicol. 2013; I: 1004-1017

Li XC., Wang CH., Leite A. P. O., Zhuo J. L. Intratubular, Intracellular, and Mitochondrial Angiotensin II/AT1 (AT1a) Receptor/NHE3 Signaling Plays a Critical Role in Angiotensin II-Induced Hypertension and Kidney Injury. Front. Physiol. 2021; 12: 702797.

De Mello, WC., Danser, AHJ. Angiotensin II and the heart: on the intracrine renin-angiotensin system. Hypertension. 2000; 35: 1183– 1188.

Dobson, JG. Reduction by adenosine of the isoproterenol-induced increase in cyclic adenosine 3',5'-monophosphate formation and glycogen phosphorylase activity in rat muscle. Circ. Res.1978; 43: 785.

Berk, BC. Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. J. Am. Soc. Nephrol. 1999; (Suppl. 11), S62– S68.

Ishida M., Ishida T., Thomas SM., Berk BC. Activation of extracellular signal-regulated kinases (ERK1/2) by angiotensin II is dependent on cSrc in vascular smooth muscle cells. Circ. Res. 1998; 82: 7–12.

Marrero MB., Schieffer B., Paxton WG., Heerdt L., Berk BC., Delafontaine, P., Bernstein KE. Direct stimulation of JAK/STAT pathway by the Angiotensin AT1 receptor. Nature. 1995; 375: 247–250.

Touyz RM., El Mabrouk M., He G., Wu XH., Schiffrin EL., Mitogen-activated protein/extracellular signal-regulated kinase inhibition attenuates angiotensin II-mediated signaling and contraction in spontaneously hypertensive rat vascular smooth muscle cells. Circ. Res. 1999; 84: 505– 515.

van Kats JP., de Lannoy LM., Danser AHJ., van Meegen JR., Verdouw PD., Schalekamp MADH. Angiotensin II type (AT1) receptor-mediated accumulation of Angiotensin II in tissues and its intracellular half-life in vivo. Hypertension. 1997; 30: 42– 49.

Li XC, Carretero OA., Navar LG., Zhuo JL. AT1 receptor-mediated accumulation of extracellular angiotensin II in proximal tubule cells: role of cytoskeleton microtubules and tyrosine phosphatases. Am J Physiol. 2006; 291: F375–F383.

Ziganshin AU, Khairullin AE, Hoyle CH., Grishin SN. Modulatory Roles of ATP and Adenosine in Cholinergic Neuromuscular Transmission. Int. J. Mol. Sci. 2020; 21, 6423.

Volpe E., Battistini L., Borsellino G. Advances in T Helper 17 Cell Biology: Pathogenic Role and Potential Therapy in Multiple Sclerosis. Mediators of Inflammation. 2015.


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How to Cite
Rubio, R. (2021). The Endothelial Barrier Restricts Endocrine Actions to the Luminal Vascular Receptors: Changing the Paradigm: A Didactic Approach. European Journal of Medical and Health Sciences, 3(6), 8–16.