Microvascular Laboratory

---

Our studies aim to determine some of the ways that cells in arteries communicate with one another and specifically, at how cells control the balance between the way that arteries narrow (constrict) and enlarge (dilate). This balance is referred to as vascular tone and is the main determinant of blood pressure and thus cardiovascular disease. Coordination of vascular tone is dependent on signals passing through junctions within and between the cellular layers in arteries. Our studies correlate anatomy and function, to identify the fundamental pathways that underlie blood vessel function.

Staff and Students

Preet Chadha (Preet.Chadha@unsw.edu.au), NHMRC Postdoctoral Fellow
Lauren Howitt (l.howitt@unsw.edu.au), Research Assistant, MSc Student
Sev Senadheera (s.senadheera@unsw.edu.au), Research Assistant (p/t with Paul Bertrand)

Current Projects

• Obesity and cardiovascular disease.
• Endothelial mechanisms in vasodilator function in health and disease.
• Myogenic control mechanisms.
• Viagra and control of blood pressure?
• Glycated proteins and vascular K-channel function.
• Anaesthetics and arterial endothelial function.

Honours Projects

Project 1: Cell communication in vascular health and disease (with Dr Shaun Sandow)

Arteries consist of two main cell types; endothelial cells and smooth muscle cells. These cells communicate with each other by release of diffusible factors and by direct contact via gap junctions. The latter junctions are referred to as myoendothelial gap junctions, and recent studies show that a variety of ion channels and receptors are found very close to these junctions, implying that they interact as a functional ‘microdomain’.

This study will use anatomical methods (confocal microscopy) to examine whether the proteins at myoendothelial gap junction microdomains are altered in vascular disease, such as is found in obesity, diabetes and hypertension. Attendance at a confocal microscopy course will be required.

Project 2: Blood pressure and cyclic-nucleotide-dependent vasodilation (with Dr Tim Murphy)

Cyclic nucleotides (cAMP and cGMP) are second messengers vitally involved in smooth muscle relaxation and vasodilation caused by several neurotransmitters, hormones and autacoids. Many commonly-used anti-hypertensive medications target the cyclic nucleotide system. Some recent observations suggest increased intra-vascular pressure alters receptor-signalling in vascular smooth muscle, preferentially targetting cyclic nucleotides. This project will to examine the effect of increased pressure on cyclic-nucleotide-mediated signalling in isolated arterioles. Techniques involved include pressure myography, real-time PCR and biochemistry.

Methods

Blood pressure recording.
Calcium imaging.
Confocal and ultrastructural immunohistochemistry.
Electron microscopy.
Electrophysiology.
Monitoring in vivo vascular reactivity.
Tension and pressure myography.
RT-PCR.

Current Grants and Awards

2006-2010 NHMRC RD Wright Biomedical Career Development Award
2007-2009 NHMRC Project Grant (CIA with Prof Margaret Morris)
2008-2010. NHMRC Project Grant (CIB with Prof Caryl Hill).
2009-2012. NHMRC Project Grant (CIC with Drs Marianne Tare, CIA, Helena Parkington, CIB and Prof Permezel).

Collaborators

• Prof Margaret Morris (M.Morris@unsw.edu.au), Physiology & Pharmacology, UNSW, Sydney
• Dr Dirk van Helden (Dirk.Vanhelden@newcastle.edu.au), Physiology, U of Newcastle, Newcastle & Dr Helena Parkington, Physiology, Monash University, Melbourne
• Dr Rebecca Lever (Rebecca.Lever@ulsop.ac.uk), Cardiovascular Pharmacology, U of London School of Pharmacy, UK
• Dr Marianne Tare (Marianne.Tare@med.monash.edu.au), Physiology, Monash University, Melbourne
• Prof Caryl Hill (Caryl.Hill@anu.edu.au), Neuroscience, JCSMR, Australian National University
• Prof Bob Lee (rmkwlee@mcmaster.ca), Anesthesia, McMaster University, Hamilton, Canada

Selected Publications

Sandow SL & Grayson TH (2009). An issue of isolation and culture: vascular endothelium and BKCa. American Journal of Physiology 297:H1-7.

Sandow SL, Gzik DJ & Lee RMKW (2009). Holes in the internal elastic lamina: what for? Journal of Anatomy. 214:258-266.

Sandow SL, Haddock RE, Hill CE, Chadha P, Kerr PM, Welsh DG & Plane F (2009). What’s where and why at a myoendothelial microdomain signaling complex? Clinical and Experimental Pharmacology and Physiology. 36:67-76.

Smith P, Brett SE, Luykenaar KD, Sandow SL, Marelli SP, Vigmond EJ & Welsh DG (2008). KIR channels function as electrical amplifiers in vascular smooth muscle. Journal of Physiology 586:1147-1160.

Welsh DG, Tran CH, Plane F, Sandow SL (2007). Are voltage-dependent ion channels involved in the endothelial cell control of vasomotor tone? American Journal of Physiology 293:H2007.

Murphy TV (2007). I don't need this pressure on; src-family kinases, ERK 1/2 kinase and mechanotransduction in arteries. Journal of Hypertension 25:1791-3.

Murphy TV, Kotecha N & Hill MA (2007). Endothelium-independent constriction of isolated, pressurized arterioles by Nomega-nitro-L-arginine methyl ester (L-NAME). British Journal of Pharmacology151: 602-9.

Grayson TH, Ohms SJ, Brackenbury TD, Peng KM, Pittelkow YE, Wilson SR, Sandow SL & Hill CE (2007). Vascular microarray profiling in two models of hypertension identifies Cav-1, RGS2 and RGS5 as antihypertensive targets. BMC Genomics. In Press

Parthimos D, Haddock RE, Hill CE & Griffith TM (2007). Dynamics of a three-variable nonlinear model of vasomotion: comparison of theory and experiment. Biophysical Journal 93: 1534-56.

Potocnik SJ, Jenkins N, Murphy TV & Hill MA (2007). Membrane cholesterol depletion with beta-cyclodextrin impairs pressure-induced contraction and calcium signalling in isolated skeletal muscle arterioles. Journal of Vascular Research 44: 292-302.

Sandow SL & Tare M (2007). CNP - a new EDHF Trends in Pharmacological Science 28: 61-67.

Hill MA, Davis MJ, Meininger GA, Potocnik SJ & Murphy TV (2006). Arteriolar myogenic signalling mechanisms: implications for local vascular function. Clinical Hemorheology and Microcirculation 34: 67-79.

Sandow SL, Neylon CB, Chen MX & Garland CJ (2006). Spatial separation of endothelial small- and intermediate-conductance calcium-activated potassium channels (KCa) and connexins: possible relationship to vasodilator function? Journal of Anatomy 209: 689-698.

Haddock RE, Grayson TH, Brackenbury TD, Meaney KR, Neylon CB, Sandow SL & Hill CE (2006). Endothelial coordination of cerebral vasomotion via myoendothelial gap junctions containing connexins37 and 40. American Journal of Physiology 291: H2047-2056. (Note: Editorial reply in same issue, pp. H2036-2038).

McNeish AJ, Sandow SL, Neylon CB, Chen, MX, Dora, KA & Garland CJ (2006). Evidence for involvement of both IKCa and SKCa channels in hyperpolarizing responses of the rat middle cerebral artery. Stroke 37: 1277-1282.

Mather S, Dora KA, Sandow SL, Winter P & Garland CJ. (2005). Rapid endothelial cell-selective loading of connexin 40 antibody blocks EDHF dilation in rat small mesenteric arteries. Circulation Research 97: 399-407.

Sandow SL, Goto K, Rummery NM & Hill CE. (2004). Developmental dependence of EDHF on myoendothelial gap junctions in the saphenous artery of the WKY rat. Journal of Physiology. 556: 875-886.

Sandow SL. (2004). Factors, fiction and endothelium-derived hyperpolarizing factor. Clinical and Experimental Pharmacology and Physiology. 31: 563-570.

Spurrell BE, Murphy TV & Hill MA (2003). Intraluminal pressure stimulates MAP kinase phosphorylation in arterioles: temporal dissociation from myogenic contractile response. American Journal of Physiology, 285: H1764-H1773.

Richards K, Davis MJ, Potocnik SJ, Murphy TV, Bishara NB, Sharmini Rajanayagam MA, Darby IA & Hill MA (2003). Approaches for introducing peptides into intact and functional arteriolar smooth muscle: manipulation of protein kinase-based signalling. Clinical and Experimental Pharmacology and Physiology, 30: 653-658.

Sandow SL, Looft-Wilson R, Grayson TH, Segal SS & Hill CE (2003). Expression of homocellular and heterocellular gap junctions in hamster arterioles and feed arteries. Cardiovascular Research. 60: 643-653.

Sandow SL, Bramich N, Bandi HP, Rummery N & Hill CE. (2003). Structure, function and EDHF in the caudal artery of the SHR and WKY rat. Arteriosclerosis, Thrombosis and Vascular Biology. 23: 822-828.

Bishara NB, Murphy TV & Hill MA (2002). Capacitative Ca2+ entry in vascular endothelial cells is mediated via pathways sensitive to 2-aminodiphenylethoxy borate and xestospongin C. British Journal of Pharmacology, 135: 119-128.

Murphy TV, Spurrell BE & Hill MA (2002). Mechanisms underlying pervanadate-induced contraction of rat cremaster arterioles. European Journal of Pharmacology, 442: 107-114.

Murphy TV, Spurrell BE & Hill MA (2002). Cellular signalling in arteriolar myogenic constriction: involvement of tyrosine-phosphorylation pathways. Clinical and Experimental Pharmacology and Physiology, 29: 612-619.

Bishara NB, Dunlop ME, Murphy TV, Darby IA, Rajanayagam MAS & Hill MA (2002). Matrix protein glycation impairs agonist-induced intracellular Ca2+ signalling in endothelial cells. Journal of Cellular Physiology, 193: 80-92.

Sandow SL, Tare M, Coleman HC, Hill CE & Parkington HC. (2002). Involvement of myoendothelial gap junctions in the actions of endothelium-derived hyperpolarizing factor. Circulation Research. 90: 1108-1113.

Murphy TV, Spurrell BE & Hill MA (2001). Tyrosine phosphorylation following alterations in arteriolar intraluminal pressure and wall tension. American Journal of Physiology, 281: H1047-1056.

Sandow SL & Hill CE. (2000). The incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in EDHF-mediated responses. Circulation Research. 86: 341-346. (Note: Editorial reply in same issue, pp. 249-250).